Journal articles: 'Monocytic lipid metabolism'

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Nakagawa, Kiyotaka, Jean-Marc Zingg, Sharon H. Kim, Michael J. Thomas, Gregory G. Dolnikowski, Angelo Azzi, Teruo Miyazawa, and Mohsen Meydani. "Differential cellular uptake and metabolism of curcuminoids in monocytes/macrophages: regulatory effects on lipid accumulation." British Journal of Nutrition 112, no. 1 (April 11, 2014): 8–14. http://dx.doi.org/10.1017/s0007114514000567.

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We have previously shown that curcumin (CUR) may increase lipid accumulation in cultured human acute monocytic leukaemia cell line THP-1 monocytes/macrophages, but that tetrahydrocurcumin (THC), an in vivo metabolite of CUR, has no such effect. In the present study, we hypothesised that the different cellular uptake and/or metabolism of CUR and THC might be a possible explanation for the previously observed differences in their effects on lipid accumulation in THP-1 monocytes/macrophages. Chromatography with tandem MS revealed that CUR was readily taken up by THP-1 monocytes/macrophages and slowly metabolised to hexahydrocurcumin sulphate. By contrast, the uptake of THC was low. In parallel with CUR uptake, increased lipid uptake was observed in THP-1 macrophages but not with the uptake of THC or another CUR metabolite and structurally related compounds. From these results, it is possible to deduce that CUR and THC are taken up and metabolised differently in THP-1 cells, which determine their biological activity. The remarkable differential cellular uptake of CUR, relative to THC and other similar molecules, may imply that the CUR uptake into cells may occur via a transporter.

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Sang, Yongming, Raymond Rowland, and Frank Blecha. "Antiviral regulation in porcine monocytic cells at different activation states (INC8P.430)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 187.3. http://dx.doi.org/10.4049/jimmunol.192.supp.187.3.

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Abstract Many pandemic viruses are monocytotropic, including porcine reproductive and respiratory syndrome virus (PRRSV), which directly infects subsets of macrophages and DCs and interferes in antiviral responses. To study antiviral responses in PRRSV-infected monocytic cells, we characterized inflammatory cytokine responses and genome-wide profiled signature genes to investigate response pathways in uninfected and PRRSV-infected monocytic cells at different activation states. Our findings showed suppressed interferon (IFN) production in macrophages at non-antiviral states and an arrest of lipid metabolic pathways in macrophages at antiviral states. Importantly, porcine monocytic cells at different activation states were susceptible to PRRSV and responded to viral infection differently. Based on gene ontology analysis, two approaches were used: 1) pharmaceutical modulation of cellular lipid metabolism and 2) in situ PRRSV replication-competent expression of IFN-α; both approaches significantly suppressed exogenous viral infection in monocytic cells. In particular, the engineered IFN-expressing PRRSV strain eliminated exogenous virus infection and sustained cell viability at 4 days post infection in macrophages. These findings suggest an intricate interaction of viral infection with activation status of porcine monocytic cells. An understanding and integration of antiviral infection with activation status of monocytic cells may provide a means of potentiating antiviral immunity.

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Thomas, A. W., N. A. Davies, H. Moir, L. Watkeys, J. S. Ruffino, S. A. Isa, L. R. Butcher, M. G. Hughes, K. Morris, and R. Webb. "Exercise-associated generation of PPARγ ligands activates PPARγ signaling events and upregulates genes related to lipid metabolism." Journal of Applied Physiology 112, no. 5 (March 1, 2012): 806–15. http://dx.doi.org/10.1152/japplphysiol.00864.2011.

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The aim of the present study was to test the hypotheses that exercise is associated with generation of peroxisome proliferator-activated receptor-γ (PPARγ) ligands in the plasma and that this may activate PPARγ signaling within circulating monocytes, thus providing a mechanism to underpin the exercise-induced antiatherogenic benefits observed in previous studies. A cohort of healthy individuals undertook an 8-wk exercise-training program; samples were obtained before (Pre) and after (Post) standardized submaximal exercise bouts (45 min of cycling at 70% of maximal O2 uptake, determined at baseline) at weeks 0, 4, and 8. Addition of plasma samples to PPARγ response element (PPRE)-luciferase reporter gene assays showed increased PPARγ activity following standardized exercise bouts (Post/Pre = 1.23 ± 0.10 at week 0, P < 0.05), suggesting that PPARγ ligands were generated during exercise. However, increases in PPARγ/PPRE-luciferase activity in response to the same standardized exercise bout were blunted during the training program (Post/Pre = 1.18 ± 0.14 and 1.10 ± 0.10 at weeks 4 and 8, respectively, P > 0.05 for both), suggesting that the relative intensity of the exercise may affect PPARγ ligand generation. In untrained individuals, specific transient increases in monocyte expression of PPARγ-regulated genes were observed within 1.5–3 h of exercise (1.7 ± 0.4, 2.6 ± 0.4, and 1.4 ± 0.1 fold for CD36, liver X receptor-α, and ATP-binding cassette subfamily A member 1, respectively, P < 0.05), with expression returning to basal levels within 24 h. In contrast, by the end of the exercise program, expression at the protein level of PPARγ target genes had undergone sustained increases that were not associated with an individual exercise bout (e.g., week 8 Pre/ week 0 Pre = 2.79 ± 0.61 for CD36, P < 0.05). Exercise is known to upregulate PPARγ-controlled genes to induce beneficial effects in skeletal muscle (e.g., mitochondrial biogenesis and aerobic respiration). We suggest that parallel exercise-induced benefits may occur in monocytes, as monocyte PPARγ activation has been linked to beneficial antidiabetic effects (e.g., exercise-induced upregulation of monocytic PPARγ-controlled genes is associated with reverse cholesterol transport and anti-inflammatory effects). Thus, exercise-triggered monocyte PPARγ activation may constitute an additional rationale for prescribing exercise to type 2 diabetes patients.

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Al-Roub, Areej, Nadeem Akhter, Amnah Al-Sayyar, Ajit Wilson, Reeby Thomas, Shihab Kochumon, Fatema Al-Rashed, Fahd Al-Mulla, Sardar Sindhu, and Rasheed Ahmad. "Short Chain Fatty Acid Acetate Increases TNFα-Induced MCP-1 Production in Monocytic Cells via ACSL1/MAPK/NF-κB Axis." International Journal of Molecular Sciences 22, no. 14 (July 19, 2021): 7683. http://dx.doi.org/10.3390/ijms22147683.

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Short-chain fatty acid (SCFA) acetate, a byproduct of dietary fiber metabolism by gut bacteria, has multiple immunomodulatory functions. The anti-inflammatory role of acetate is well documented; however, its effect on monocyte chemoattractant protein-1 (MCP-1) production is unknown. Similarly, the comparative effect of SCFA on MCP-1 expression in monocytes and macrophages remains unclear. We investigated whether acetate modulates TNFα-mediated MCP-1/CCL2 production in monocytes/macrophages and, if so, by which mechanism(s). Monocytic cells were exposed to acetate with/without TNFα for 24 h, and MCP-1 expression was measured. Monocytes treated with acetate in combination with TNFα resulted in significantly greater MCP-1 production compared to TNFα treatment alone, indicating a synergistic effect. On the contrary, treatment with acetate in combination with TNFα suppressed MCP-1 production in macrophages. The synergistic upregulation of MCP-1 was mediated through the activation of long-chain fatty acyl-CoA synthetase 1 (ACSL1). However, the inhibition of other bioactive lipid enzymes [carnitine palmitoyltransferase I (CPT I) or serine palmitoyltransferase (SPT)] did not affect this synergy. Moreover, MCP-1 expression was significantly reduced by the inhibition of p38 MAPK, ERK1/2, and NF-κB signaling. The inhibition of ACSL1 attenuated the acetate/TNFα-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. Increased NF-κB/AP-1 activity, resulting from acetate/TNFα co-stimulation, was decreased by ACSL1 inhibition. In conclusion, this study demonstrates the proinflammatory effects of acetate on TNF-α-mediated MCP-1 production via the ACSL1/MAPK/NF-κB axis in monocytic cells, while a paradoxical effect was observed in THP-1-derived macrophages.

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Todd, R. F., P. A. Alvarez, D. A. Brott, and D. Y. Liu. "Bacterial lipopolysaccharide, phorbol myristate acetate, and muramyl dipeptide stimulate the expression of a human monocyte surface antigen, Mo3e." Journal of Immunology 135, no. 6 (December 1, 1985): 3869–77. http://dx.doi.org/10.4049/jimmunol.135.6.3869.

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Abstract Exposure of mononuclear phagocytes to bacterial lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or muramyl dipeptide (MDP) is known to stimulate a variety of cellular activities that include increases in phagocytosis, oxidative metabolism, synthesis and secretion of monokines, and cytotoxicity of microbes and tumor cells. We now report that culture of human peripheral blood monocytes in medium containing LPS, phorbol compounds, or MDP also results in the acquired expression of a plasma membrane antigen. Mo3e, as identified by a murine monoclonal antibody. Mo3e is barely detectable (by immunofluorescence flow cytometry) on freshly isolated monocytes, but is expressed in high antigen density after exposure of cells to E. coli, Salmonella minnesota, or Serratia marcescens LPS (at concentrations exceeding 0.1 ng/ml), PMA (and other biologically active phorbol compounds) (0.5 to 1 X 10(-8) M), or MDP (0.01 to 1 X 10(-6) M). Mo3e expression stimulated by LPS is prevented by pretreatment of LPS with polymyxin B, suggesting that the lipid A portion of LPS is responsible for Mo3e induction (polymyxin B has no effect on Mo3e expression stimulated by PMA or MDP). Culture of monocytes in medium containing protein synthesis inhibitors (or at 4 degrees C) blocks the acquisition of Mo3e. Recombinant IFN-gamma, which is also known to "activate" mononuclear phagocytes, does not stimulate Mo3e expression, although both LPS and IFN induce enhanced expression of monocyte Ia antigen. Analogous to their stimulatory effect on monocytes, LPS and PMA induce Mo3e expression by the human monocytic cell line, U-937. On the basis of these observations, Mo3e may represent an immunologic marker for monocyte activation stimulated in vitro by LPS, PMA (and related compounds), and MDP.

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BENGTSSON, Sara H. M., Katja MADEYSKI-BENGTSON, Jeanette NILSSON, and Gunnar BJURSELL. "Transcriptional regulation of the human carboxyl ester lipase gene in THP-1 monocytes: an E-box required for activation binds upstream stimulatory factors 1 and 2." Biochemical Journal 365, no. 2 (July 15, 2002): 481–88. http://dx.doi.org/10.1042/bj20020223.

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The bile salt-stimulated carboxyl ester lipase (CEL) is important for the digestion and absorption of dietary lipids, and is expressed at high levels by the exocrine pancreas and the lactating mammary gland. However, the presence of CEL in human plasma suggests that the role of CEL in lipid metabolism may stretch beyond its function in the intestinal lumen, and possibly include interactions with cholesterol and oxidized lipoproteins to modulate the progression of atherosclerosis. We have used the CEL-expressing human monocytic cell line THP-1 to investigate the transcriptional regulation of the human CEL in monocytes. Analyses of the promoter region revealed that an E-box located at −47/−52 is necessary for CEL expression. Point mutations in the E-box almost completely abolish the transcriptional activity. Electrophoretic mobility-shift assay analyses reveal that the E-box binds the upstream stimulatory factors 1 and 2, and the binding of an upstream stimulatory factor-containing complex in THP-1 cells also requires the presence of a putative nuclear receptor-binding site at −60/−66. Furthermore, we demonstrate that the E-box is also necessary for CEL expression in the pancreas and the mammary gland, although there are tissue-specific requirements for additional activating elements.

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Jin, Linhua, Yoko Tabe, Marina Konopleva, Michael Andreeff, Akimichi Ohsaka, and Takashi Miida. "Bone Marrow-Derived Adipocytes Promote Differentiation, Proliferation and Survival of Acute Monoblastic Leukemia Cells." Blood 118, no. 21 (November 18, 2011): 1501. http://dx.doi.org/10.1182/blood.v118.21.1501.1501.

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Abstract Abstract 1501 Acute monoblastic leukemia occurs most commonly in young individuals, whereas acute monocytic leukemia is common in adults (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2008). Adipocytes are the prevalent stromal cell type in adult bone marrow (BM) and play an important role in the leukemic bone marrow microenvironment (Tabe et al., Blood 2004 103: 1815–22). BM stromal cells (MSCs) from elderly subjects have a reduced capacity to differentiate into osteoblasts and an increased capacity to differentiate into adipocytes, which leads to progressive accumulation of fat in the BM space with increasing age. In this study, we examined whether BM-derived adipocytes participate in the molecular events associated with proliferation, differentiation and apoptosis of monoblastic leukemia cells. To this end, we performed gene expression microarray analysis of 339 genes associated with lipid metabolism (GeneSQUARE, Kurabo, Japan) using RNA from monoblastic leukemia cell line U937 co-cultured with MSC or MSC-derived adipocytes. Five genes were upregulated (>2.0 fold) and 2 genes down-regulated in U937 cells co-cultured with adipocytes compared to U937 cultured alone. The up-regulated genes included monocyte/macrophage differentiation specific genes, such as scavenger receptor CD36, adipsin or fatty acid binding protein 4 (FABP4). CD36 and FABP4 are classical target genes of PPARγ which was also upregulated in U937 co-cultured with adipocytes. Upregulation of the inflammation-related haptoglobin gene was observed in U937 cells co-cultured with either adipocytes or MSC. These findings were confirmed by quantitative RT-PCR assay with concordant results. Down-regulated genes included monocyte chemoattractant protein-1 (MCP-1) (0.1 fold) and glycolytic enzyme hexokinase 2 (0.4 fold). In turn, U937 cells co-cultured with premature or mature adipocytes accumulated in G2 cell cycle phase compared to U937 cultured alone or co-cultured with MSC (% G2/M-phase fraction; U937 cultured alone, 14.6, co-culture with MSC 25.1, co-culture with preadipocyte 32.0, with mature adipocyte 31.9) and were protected from spontaneous cell death under serum-starved conditions (% subG1 fraction: U937 cultured alone 23.9%, co-cultured with MSC 15.7%, with preadipocytes 3.9% and with mature adipocytes 11.6%). In summary, results suggest that BM adipocytes, abundant in adult BM space, promote monocytic differentiation, proliferation and survival of monoblastic leukemia cells. We propose that these cells represent an essential component of the BM microenvironment that contributes to malignant phenotypes of adults with monocytic leukemia. Disclosures: No relevant conflicts of interest to declare.

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Strauss, Laura, Jessica D. Weaver, Rinku Pal, John Asara, Nikolaos Patsoukis, and Vassiliki A. Boussiotis. "Metabolic Reprogramming of Myeloid Cells in Response to Factors of "Emergency" Myelopoiesis By Myeloid-Specific PD-1 Ablation, Regulates Myeloid Lineage Fate Commitment and Anti-Tumor Immunity." Blood 132, Supplement 1 (November 29, 2018): 14. http://dx.doi.org/10.1182/blood-2018-99-117438.

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Abstract PD-1 is a T cell inhibitor for which blocking agents have achieved success as anti-cancer therapeutics. The current view is that cancer limits host immune responses by upregulating PD-L1 in the tumor microenvironment (TME) thereby causing PD-1 ligation and inactivation of CD8+ Teff cells. However, PD-L1 expression in the TME does not always correlate with therapeutic response. Thus, the mechanism(s) by which PD-1 blockade reverses compromised anti-tumor immunity are poorly understood. The rapid increase in hematopoietic cell output that occurs in response to immunologic stress is known as emergency myelopoiesis. Low-level stimulation by cancer-generated factors induces modest but continuous expansion of myeloid progenitors (MP) (common myeloid progenitors (CMP) and granulocyte/macrophage progenitors (GMP)) albeit with hindered differentiation, leading to output of tumor-promoting myeloid-derived suppressor cells (MDSCs). We determined that myeloid cells expanding during cancer-driven emergency myelopoiesis in tumor-bearing mice express PD-1 and PD-L1. Using PD-1 KO mice we found that PD-1 deletion prevented the accumulation of GMP and stimulated the output of Ly6Chi effector monocytes, macrophages and dendritic cells (DC). To determine whether these outcomes were mediated by a myeloid-intrinsic impact of PD-1 ablation or by the effects of PD-1neg T cells on myeloid cells, we generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells (PD-1f/fLysMcre) or T cells (PD-1f/fCD4cre). Myeloid-specific, but not T cell-specific PD-1 ablation, prevented the accumulation of GMP while promoting the output of effector-like myeloid cells expressing CD80, CD86, CD16/32 (FcRII/III) and CD88 (C5aR). Myeloid cells with PD-1 ablation had elevated expression of IRF8 that drives monocyte and DC differentiation and decreased expression of the MDSC hallmark markers IL-4R, CD206, ARG1 and CD38. Nutrient utilization has a decisive role on the fate of hematopoietic progenitors (HP) and MP. Stemness and pluripotency are regulated by maintenance of glycolysis whereas switch to mitochondrial metabolism is associated with differentiation. To examine whether PD-1 ablation affected these metabolic proceces, bone marrow (BM) from PD-1f/f and PD-1f/fLysMcre mice was cultured with G-CSF/GM-CSF/IL-6, key drivers of emergency myelopoiesis. MP differentiation was documented by decrease of Linneg and increase of Linpos cells, which was more prominent in PD-1f/fLysMcre BM cultures. This coincided with increase of CD45+CD11b+ and dominance of Ly6C+ monocytic cells consistent with a cell-intrinsic mechanism of monocytic lineage commitment. PD-1f/fLysMcre MP had elevated mTORC1, Erk1/2 and Stat1 activation, and enhanced glucose uptake and mitochondrial biogenesis. Bioenergetics studies showed robust development of a mitochondrial-dominant profile, consistent with metabolism-driven enhanced differentiation of MP. Mass spectrometry revealed enhanced intermediates of glycolysis, PPP and TCA cycle, but the most prominent difference was the increased cholesterol. Because mTORC1 signaling, which was enhanced in PD-1f/fLysMcre MP, activates de novo lipid and cholesterol synthesis via SREBP1, we examined the mevalonate pathway of cholesterol synthesis. mRNA for genes mediating cholesterol synthesis and uptake was increased whereas mRNA for genes mediating cholesterol metabolism was decreased. Cholesterol induces a proinflammatory program in myeloid cells, drives differentiation of monocytes, macrophages and DC and promotes antigen-presenting function. We examined how such changes in myeloid cells might affect the function of T cells, which are key anti-tumor mediators. Compared to tumor-bearing PD-1f/f mice, PD-1f/fLysMcre tumor-bearers had no quantitative T cell differences but had an increase in IFNγ- IL-17-, and IL-10-expressing CD8+ Teff-mem and IL-2-expressing Tcentral-mem cells, consistent with superior functionality. These changes correlated with enhanced anti-tumor protection despite preserved PD-1 expression in T cells. Our findings reveal a previously unidentified role of PD-1 in metabolism-driven myeloid cell lineage fate commitment and differentiation and suggest that switch to effector myeloid cells might be a key mechanism by which PD-1 blockade mediates systemic anti-tumor immunity. Disclosures No relevant conflicts of interest to declare.

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Spinelli, Sherry L., Stephen J. Pollock, Thomas I. Murant, Jamie J. O’Brien, Neil Blumberg, Charles W. Francis, Mark B. Taubman, Denise M. Ray, and Richard P. Phipps. "Peroxisome proliferator-activated receptor γ and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles." Thrombosis and Haemostasis 99, no. 01 (2008): 86–95. http://dx.doi.org/10.1160/th07-05-0328.

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SummaryPeroxisome proliferator-activated receptor γ (PPARγ) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARγ and that PPARγ ligands blunt platelet activation. To further understand the nature of PPARγ in platelets, we determined the platelet PPARγ isoform(s) and investigated the fate of PPARγ following platelet activation. Our studies demonstrated that human platelets contain only the PPARγ1 isoform and after activation with thrombin, TRAP, ADP or collagen PPARγ is released from internal stores. PPARγ release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARγ was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARγ and RXR were microparticle associated and the released PPARγ/RXR complex retained DNA-binding ability. Additionally, a monocytic cell line, THP-1, is capable of internalizing PMPs. Further investigation following treatment of these cells with the PPARγ agonist, rosiglitazone and PMPs revealed a possible transcellular mechanism to attenuate THP-1 activation. These new findings are the first to demonstrate transcription factor release from platelets, revealing the complex spectrum of proteins expressed and expelled from platelets, and suggests that platelet PPARγ has an undiscovered role in human biology.

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Tabe, Yoko, Masako Harada, Yuka Miyamae, Kaoru Mogushi, Saiko Kazuno, Tsutomu Fujimura, Hiromichi Matsushita, et al. "Bone Marrow Adipocyte-Derived Free Fatty Acids Induce Gene Signature Linking Transcription with Metabolic Changes That Contribute to Survival of Acute Monocytic Leukemia Cells." Blood 124, no. 21 (December 6, 2014): 1013. http://dx.doi.org/10.1182/blood.v124.21.1013.1013.

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Abstract Adipocytes are the prevalent stromal cell type in adult bone marrows (BM). With increasing age, BM stroma-resident mesenchymal stem cells (MSCs), increase their capacity to differentiate into adipocytes, which leads to the progressive accumulation of fat in the BM space. It is conceivable that the increased BM adipocyte content promotes leukemogenesis and negatively affects responsiveness to chemotherapy. We previously reported that free fatty acids (FFAs) promote the metabolic shift from pyruvate oxidation to fatty acid oxidation (FAO), which causes uncoupling of mitochondrial oxidative phosphorylation and promotes leukemia cell survival (Samudio, J Clin Invest. 2010). We further demonstrated the prominent antiapoptotic effects of BM-derived adipocytes co-cultured with cells from acute monocytic leukemia (AMoL), a poor-prognosis subtype of AML (Tabe ASH. 2013). Proteomic analysis with isobaric tags for relative and absolute quantification (iTRAQ) showed upregulation of protein folding pathways which increases the expression of antiapoptotic chaperone proteins HSP70 and HSP90, of integrin-mediated cell adhesion and migration pathways and downregulation of oxidative phosphorylation along with repression of cytochrome c.Metacore gene ontology (GO) analysis identified NF-kB, c-Jun, SP1, AP-1, and HMG as the potent relevant transcription factors that closely interact with and activate chaperone proteins, chromatin, and gene transcription. In this study, we characterized a gene signature linking transcription with metabolic changes that contribute to AMoL cell survival under conditions mimicking aging BM with prevalent adipocytes. We confirmed the antiapoptotic role of FFAs produced by the primary BM MSC-derived adipocytes via pharmacologic inhibition of FAO by etomoxir (EX), which inhibits fatty acid entry into the mitochondria. EX (50mM) treatment reversed the prosurvival effects of adipocytes on serum-starved U937 monoblast cells (% Annexin V, -/+ EX: mono-culture, 30.1±9.0 / 31.5±4.6; co-culture with adipocytes, 8.9±2.1 / 29.6±9.2; P=0.02). To assess the molecular links between metabolic pathways and gene expression triggered by BM adipocytes, we performed RNA-seq transcriptome analysis with a next generation sequencer system HiSeq1500 (Illumina) using TopHat software for alignment and Cufflinks software for identifying differential gene expression. RNA-Seq detected upregulation of 21 genes in U937 cells after co-culture with BM-derived adipocytes (false discovery rate, <0.05). Specifically, 10 of these upregulated genes were significantly decreased by EX treatment, including transcription factor–activating PPARg2 promoter KLF9, co-chaperone immunophilin protein FKBP5, chemokine CXCL12 receptor CXCR4, receptor tyrosine kinase FLT3, PI3K negative regulator PIK3IP1, and immunosuppressive transcriptional regulator TSC22D3. GO pathway analysis further revealed that co-culture with adipocytes induced upregulation of antioxidant thioredoxin peroxidase activity, which was reversed by EX. Together with the iTRAQ GO results, the antioxidative chaperone proteins might play critical roles in regulation of FAO with repression of oxidative phosphorylation in AMoL cells in adipocytes abundant BM. DNA array (GeneSQUARE) analysis and quantitative RT-PCR detected upregulation of fatty acid binding protein 4 (FABP4), scavenger receptor CD36, nuclear receptor PPARG, and antiapoptotic Bcl-2 in U937 cells co-cultured with adipocytes. It is known that FFAs, the ligand of nuclear receptor PPARγ, activate PPARγ and promote FFA uptake through transcriptional induction of CD36 and FABP4 in monocytic cells. EX treatment, which blocks the entry of fatty acids into the mitochondria, induced prominent elevation of FABP4 in U937 cells co-cultured with adipocytes. These results indicate that the FABP4-mediated internalization and ligation of fatty acids to PPARγ facilitates transcriptional activation. From the transcriptome analysis and the mitochondrial uncoupling metabolic changes, we conclude that the survival of AMoL cells depends on the cooperative interactions between lipid metabolism and transcriptional activation of factors associated with chaperones, chemokines, and integrins. Strategies targeting FAO warrant further exploration in patients with monocytic leukemia, which is highly dependent on altered lipid metabolism. Disclosures No relevant conflicts of interest to declare.

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Mousa, Hanaa, Nazmul Islam, Vijay Ganji, and Susu M. Zughaier. "Serum 25-Hydroxyvitamin D Is Inversely Associated with Monocyte Percentage to HDL Cholesterol Ratio among Young Healthy Adults in Qatar." Nutrients 13, no. 1 (December 31, 2020): 127. http://dx.doi.org/10.3390/nu13010127.

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Low serum 25-hydroxyvitamin D [25(OH)D] is linked to an altered lipid profile. Monocytes play an important role in inflammation and lipid metabolism. Recently, monocyte percentage to HDL-cholesterol ratio (MHR) has emerged as a novel marker of inflammation. We investigated the association between serum 25(OH)D concentrations and MHR and serum lipids in young healthy adults. Data from the Qatar Biobank were utilized to investigate the relation between serum 25(OH)D and inflammation and serum lipid concentrations in healthy Qatari adults using multivariate regression analysis. Prevalence of serum 25(OH)D concentrations <12 ng/mL (deficiency), 12–20 ng/mL (insufficiency), and ≥20 ng/mL (sufficiency) were 55.8%, 29.9%, and 14.3%, respectively. Serum 25(OH)D was significantly inversely associated with monocyte percentage, MHR, total cholesterol, LDL-cholesterol, and triacylglycerol in multivariable adjusted analysis. MHR could be a potential biomarker to predict cardiometabolic diseases among young healthy Qataris.

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Tabe, Yoko, Marina Konopleva, Norikazu Monma, Kazuho Ikeo, Kaoru Mogushi, Yasunari Yamanaka, Hiromichi Matsushita, Takashi Miida, Yoshihide Hayashizaki, and Michael Andreeff. "Cap Analysis of Gene Expression (CAGE) Sequencing Reveals Alterations of the Transcript Signatures in Acute Monocytic Leukemia Cells By Fatty Acid Oxidation Inhibition." Blood 126, no. 23 (December 3, 2015): 3631. http://dx.doi.org/10.1182/blood.v126.23.3631.3631.

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Abstract Adipocytes, differentiated from bone marrow (BM) stroma-resident mesenchymal stem cells (MSC), are the prevalent stromal cell type in adult BM that increase with aging and cause leukemia cell resistance to chemotherapy (Ehsanipour Cancer Res. 2013). We previously reported that MSC-derived adipocytes prominently inhibited the spontaneous apoptosis of co-cultured acute monocytic leukemia (AMoL) cells, a poor-prognosis subtype of AML, and that a pharmacologic fatty acid oxidation (FAO) inhibitor Etomoxir (EX) reversed the prosurvival effects of adipocytes, indicating the importance of FAO dependent metabolic alterations in AMoL survival (Tabe ASH. 2014). To assess the transcription factors responsible for AMoL cell survival in adipocyte co-culture condition and for apoptosis induction by FAO inhibition, the alterations of transcript signatures were examined by the cap analysis of gene expression (CAGE) sequencing utilizing second-generation sequencing platform (Illumina Genome Analyzer). CAGE identifies and quantifies the 5' ends of capped mRNA transcripts, which enables the identification of transcription start sites (TSS) and allows investigating promoter structures necessary for gene expression (Carninci et al. 1996). The TSS of genes altered in U937 and THP1 cells co-cultured with adipocytes in the presence or absence of EX were mapped, and the common alterations observed in both cell types were analyzed. CAGE detected upregulation of 366 genes and downregulation of 219 genes after co-culture with adipocytes (false discovery rate, < 0.05). Ingenuity Pathway Analysis (IPA) revealed that adipocyte co-culture activated the cancer associated transcription factors Myc and FOXM1, and inhibited the p53 transcription regulator IFI16 and FLT1 kinase, an upstream positive regulator of MAPK/ERK and PI3K/AKT signaling. After EX treatment, CAGE-IPA analysis implicated inhibition of the FAO initiation enzyme ACOX1, and activation of the transcription factor ATF4 (Activating Transcription Factor 4), the master coordinator of the integrated stress response (ISR), and of the nuclear receptor PPARG which controls the FAO pathway. To narrow down the specific transcription factors responsible for EX induced apoptosis in AMoL cells co-cultured with adipocytes, CAGE-mapped TTS signature was integrated with the gene expression patterns detected by RNA-seq. CAGE and RNA-seq detected 3 genes consistently upregulated by adipocyte co-culture (KLF9; a transcription factor that activates PPARg2 promoter, FKBP5; HSP90 interacting co-chaperone immunophilin protein, ATP13A2; a member of the P5 subfamily of ATPases) and downregulation of 2 genes (ANPEP; known as CD13 or Alanyl Aminopeptidase, SLC39A10; Zinc transporter which involves in lipid metabolism). EX treatment under adipocyte co-culture condition specifically upregulated 12 genes including ISR mediator ATF4 and its target gene TRIB3. The upregulation of asparagine syntheses gene ASNS, known to be induced by ATF4, was also detected by RNA-seq. Concordant with CAGE-IPA results, EX treatment upregulated lipid accumulation marker PLIN2 and PPARG target of fatty acid binding protein FABP4 likely reflecting the direct feedback of FAO inhibition. Two genes were downregulated by EX treatment (SREBP1; the lipogenic transcription factor, P2RY2; G-protein coupled receptor activated by ATP). Finally, capillary electrophoresis mass spectrometry (CE-MS) detected the upregulation of citric acid by adipocyte co-culture, which was significantly depleted after EX treatment. The EX treatment, however, increased lactic acid along with fructose 6-phosphate and glucose 6-phosphate upregulation, indicating that cellular metabolism shifts from oxidative phosphorylation and FAO to anaerobic glycolysis which is known to activate ISR. Taken together, this study demonstrates that FAO inhibition by EX activates the pro-apoptotic transcriptional program of ISR through the up-regulation of ATF4 in adipocyte co-cultured AMoL cells. The strategies targeting FAO warrant further exploration in AMoL that survives in adipocyte abundant aged adult BM. Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

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Fazylov, S. D., O. A. Nurkenov, A. E. Arinova, A. M. Gazaliev, R. E. Bakirova, M. K. Ibraev, A. Т. Takibayeva, and A. S. Fazylov. "INDICATORS OF CELL METABOLISM IN VITRO IN RESEARCHES OF ANTI-INFLAMMATORY AND CYTOTOXIC EFFECTS OF FULLEROPYRROLIDINES С60 AND THEIR INITIAL SUBSTRATES." BULLETIN 5, no. 387 (October 15, 2020): 25–33. http://dx.doi.org/10.32014/2020.2518-1467.139.

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The article considers data on the in vitro study of new fulleropyrrolidine compounds for anti-inflammatory and cytotoxic activity in cultures of human monocyte cell lines MonoMac-6 and THP-1Blue and also as inhibitors of human neutrophil elastase. This enzyme is a regulator of inflammation. In different situations, it can act both as a pro-inflammatory and as an anti-inflammatory agent. An imbalance in the regulation of elastase activity plays an important role in the pathogenesis of cystic fibrosis, acute respiratory distress syndrome, bronchiectasis, chronic obstructive pulmonary disease, type 2 diabetes mellitus, atherosclerosis and hypertension. In the future, such studies should lead to the creation of optimal in vitro models that most adequately reflect the situation in vivo and establish the relationship between the structure and activity of the studied drugs. It is noted that the presence of lipophilic properties in fullerene C60 derivatives is especially important in the development of pharmaceuticals for the control of pathogens of various infectious diseases. Fullerene C60 derivatives have the ability to easily penetrate lipid membranes, overcome the blood-brain barrier, and modulate ion transport. Compounds were tested for anti-inflammatory and cytotoxic activity (in vitro) on cultures of human monocytic cell lines MonoMac-6 and THP-1Blue. Modified fullerene compounds of various structures were tested for their inhibitory ability against neutrophil elastase enzyme (in vitro). Elastase activity was evaluated by the ability of fulleropyrrolidine compounds to hydrolyze the synthetic substrate N-methylsuccinyl-Ala-Ala-Pro-Val-7-amino-4-me-thylcoumarin (Calbiochem). The results of studies of fullerene compounds in relation to their anti-inflammatory and cytotoxic activity are obtained. The analysis of the fluorescence kinetics of the compounds was carried out. The cytotoxic activity of the samples was investigated in the Brine Schrimp test using Artemia salina. All compounds have cytotoxicity, which suggests a lack of selectivity of chemotherapeutic action. In general, the presence of a cytotoxic effect confirms the reality of antimicrobial action. The results of the study of the antibacterial and antifungal activity of the synthesized new fulleropyrrolidines and their starting substrates are described (S. aureus 505, Bacillus subtilis, Str.agalactiae, E. Coli M-17, Ps.aeruginosa, Candida аlbicans, Penicillium citrinum, Aspergillus niger, Aspergillus flavus, Trichophyton mentagraphytos, Epidermophyton fioccosum). As a result of the study of the potential antifungal activity of the compounds, it was found that only two drugs inhibit the growth of test cultures in vitro. All other studied samples have practically no activity against the yeast fungi Candida albicans. In general, the presence of a cytotoxic effect in the studied fullerene compounds confirms the reality of the antimicrobial action.

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Tabe, Yoko, Linhua Jin, Saiko Kazuno, Tsutomu Fujimura, Hiromichi Matsushita, Takashi Ueno, Michael Andreeff, Jordan U. Gutterman, and Marina Konopleva. "A Plant Triterpenoid Avicin D Stimulates Adipocytic Differentiation of Bone Marrow Stromal Cells and Promotes Their Pro-Survival Effects On Acute Monoblastic Leukemia Cells." Blood 120, no. 21 (November 16, 2012): 4315. http://dx.doi.org/10.1182/blood.v120.21.4315.4315.

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Abstract Abstract 4315 A natural triterpene Avicin D induces apoptosis in various tumor cells and regulates cellular metabolism via Glucocorticoid receptor (GR) signalling, known to be involved in adipocyte differentiation (Tang, Annu Rev Biochem. 2012;81:715). Since adipocytes represent an essential component of the aging bone marrow (BM) microenvironment (Tabe, Blood 2004;103:1815), and promote monocytic differentiation and survival of monoblastic leukemia cells (Tabe, ASH, 2011), we examined the potential of Avicin D to modulate BM adipocytes and its effects on the survival of the leukemic cells. In mature adipocytes derived from BM mesenchymal stem cells (MSCs), Avicin D (1ƒÊM, 48 hrs) significantly increased the number of lipid vesicles without apoptosis induction or significant cell cycle arrest. This was associated with upregulation of adipose-specific genes, PPARG and fatty acid binding protein 4 (FABP4), and inflammation-related haptoglobin (HP) gene (p<0.005, Figure 1). Avicin D further enhanced leptin release from adipocytes and inflammatory cytokines production, IL-6 and IL-8, from both MSCs and adipocytes (Figure 2). Of note, Avicin D increased pro-survival Bcl-2 mRNA expression in adipocytes (fold increase compared to MSCs: MSCs+Avicin D 1.0±0, adipocytes 1.8±0.1, adipocytes+Avicin D 4.4±0.6, p=0.02). We next investigated the effects of MSCs and adipocytes pre-treated with 1mM Avicn D for 24 hours on co-cultured monoblastic leukemia cell line U937. Avicin D (1ƒÊM) moderately (26±5 %) inhibited cell proliferation of U937 cells cultured alone as detected by MTT assay. Serum-starvation induced cell death in U937 cells was inhibited by MCS or adipocyte co-culture, and further blocked by Avicin D-pretreated adipocytes, which was accompanied with cell cycle arrest (sub-G1 fraction; control U937 36.1±7.1%, co-culture with MSC 17.9±4.1%, MSC+Avicin D 20.9±3.9%, adipocyte 16.9±2.9, adipocyte+Avicin D 11.5±0.8%, p=0.03, G0/G1 phase; control 39.1±5.9%, with MSC 44.3±1.0%, MSC+Avicin D 40.3±1.3%, adipocyte 40.6±1.3, adipocyte+Avicin D 50.4±2.3%, p=0.03). Co-culture of U937 cells with Avicin D-pretreated adipocytes induced upregulation of PPARG and CD36, markers of monocytes/macrophages maturation in U937 cells (fold increase compared to control U937: PPARG: co-culture with adipocytes 2.1±0.4, adipocytes+Avicin D 13.8±6.2; CD36: adipocytes 2.2±0.4, adipocytes+Avicin D 4.7±2.9). Co-culture with Avicin D-pretreated adipocytes also caused 3.1 ±0.4 fold increase of BCL2 mRNA in U937 cells compared to the one of co-cultured with control adipocytes (p=0.02). The purity of U937 cells separated from adipocytes was confirmed by lack of CD90 mRNA expression by PCR. Utilization of the proteomic technology of isobaric tags for relative and absolute quantitation (iTRAQ) with two-dimensional-liquid chromatography-tandem mass spectrometry allowed the identification of 1,634 proteins. We found changes in 14 proteins in U937 cells co-cultured with Avicin D-pretreated adipocytes compared to untreated adipocytes. Among 13 down-regulated proteins, three are involved in pyruvate metabolism (Glyoxalase I; p=0.01, Lactate dehydrogenase B; p=0.02, Pyruvate kinase; p=0.03), and four proteins participate in cell cycle progression (DNA replication licensing factor MCM4, MCM5; p=0.02, p=0.03, DNA-dependent protein kinase; p=0.02, Interleukin enhancer-binding factor 3; p=0.005). Voltage-dependent anion-selective channel protein 2, which is involved in the mitochondrial apoptotic pathway via regulation of Bcl-2, and an enzymatic antioxidant Superoxide dismutase were up-regulated (p=0.04, p=0.03). These data indicate that U937 cells co-cultured with Avicin D pretreated adipocytes were induced to undergo cell cycle arrest, escape apoptosis with down-regulation of glucose metabolism. Altogether, these results suggest that Avicin D induces adipocytic differentiation of BM-derived stromal cells, promotes production of leptin and inflammatory cytokines, which in turn supports survival of monocytic leukemia cells. These findings suggest a contributory role of the aging “pro-inflammatory” bone marrow microenvironment in the reduced efficacy of cytotoxic chemotherapy which is prevalent in elderly AML patients. Disclosures: No relevant conflicts of interest to declare.

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Koshibu, Masakazu, Yusaku Mori, Tomomi Saito, Hideki Kushima, Munenori Hiromura, Michishige Terasaki, Michiya Takada, Tomoyasu Fukui, and Tsutomu Hirano. "Antiatherogenic effects of liraglutide in hyperglycemic apolipoprotein E-null mice via AMP-activated protein kinase-independent mechanisms." American Journal of Physiology-Endocrinology and Metabolism 316, no. 5 (May 1, 2019): E895—E907. http://dx.doi.org/10.1152/ajpendo.00511.2018.

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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert potent glucose-lowering effects without increasing risks for hypoglycemia and weight gain. Preclinical studies have demonstrated direct antiatherogenic effects of GLP-1RAs in normoglycemic animal models; however, the underlying mechanisms in hyperglycemic conditions have not been fully clarified. Here we aimed to elucidate the role of AMP-activated protein kinase (AMPK) in antiatherogenic effects of GLP-1RAs in hyperglycemic mice. Streptozotocin-induced hyperglycemic apolipoprotein E-null mice were treated with vehicle, low-dose liraglutide (17 nmol·kg−1·day−1), or high-dose liraglutide (107 nmol·kg−1·day−1) in experiment 1 and the AMPK inhibitor dorsomorphin, dorsomorphin + low-dose liraglutide, or dorsomorphin + high-dose liraglutide in experiment 2. Four weeks after treatment, aortas were collected to assess atherosclerosis. In experiment 1, metabolic parameters were similar among the groups. Assessment of atherosclerosis revealed that high-dose liraglutide treatments reduced lipid deposition on the aortic surface and plaque volume and intraplaque macrophage accumulation at the aortic sinus. In experiment 2, liraglutide-induced AMPK phosphorylation in the aorta was abolished by dorsomorphin; however, the antiatherogenic effects of high-dose liraglutide were preserved. In cultured human umbilical vein endothelial cells, liraglutide suppressed tumor necrosis factor-induced expression of proatherogenic molecules; these effects were maintained under small interfering RNA-mediated knockdown of AMPKα1 and in the presence of dorsomorphin. Conversely, in human monocytic U937 cells, the anti-inflammatory effects of liraglutide were abolished by dorsomorphin. In conclusion, liraglutide exerted AMPK-independent antiatherogenic effects in hyperlipidemic mice with streptozotocin-induced hyperglycemia, with the possible involvement of AMPK-independent suppression of proatherogenic molecules in vascular endothelial cells.

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Králíčková, Pavlína, Hana Kalábová, Lenka Krčmová, Markéta Kašparová, Jiří Plíšek, Leoš Ungermann, Doris Vokurková, et al. "Correlation of Peripheral Blood CD14+CD16+ Monocytes, Urinary Neopterin and the Risk Factors of Atherosclerosis in Patients with Breast Carcinoma." Pteridines 22, no. 1 (February 2011): 66–72. http://dx.doi.org/10.1515/pteridines.2011.22.1.66.

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Abstract Monocytes/macrophages are thought to play a fundamental role in the development of vascular lesions in atherosclerosis. In the present study, we evaluated circulating CD14+CD16+ monocytes, laboratory parameters of the risk of atherosclerosis, including serum cholesterol, homocysteine and C-reactive protein, urinary neopterin, serum a-tocopherol and retinol along with carotid intima-media thickness in patients with breast carcinoma. A significant correlation was observed between the absolute numbers of CD14+CD16+ monocytes, serum HDL cholesterol and triglyceride concentrations. In conclusion, present data extend the observation of an association between peripheral blood CD14+CD16+ monocyte counts and lipid metabolism to cancer patients. No correlation of CD14+CD16+ monocyte counts with urinary neopterin concentrations was observed.

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Khan, Ilvira M., Yashashwi Pokharel, Razvan T. Dadu, Dorothy E. Lewis, Ron C. Hoogeveen, Huaizhu Wu, and Christie M. Ballantyne. "Postprandial Monocyte Activation in Individuals With Metabolic Syndrome." Journal of Clinical Endocrinology & Metabolism 101, no. 11 (August 30, 2016): 4195–204. http://dx.doi.org/10.1210/jc.2016-2732.

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Context: Postprandial hyperlipidemia has been suggested to contribute to atherogenesis by inducing proinflammatory changes in monocytes. Individuals with metabolic syndrome (MS), shown to have higher blood triglyceride concentration and delayed triglyceride clearance, may thus have increased risk for development of atherosclerosis. Objective: Our objective was to examine fasting levels and effects of a high-fat meal on phenotypes of monocyte subsets in individuals with obesity and MS and in healthy controls. Design, Setting, Participants, Intervention: Individuals with obesity and MS and gender- and age-matched healthy controls were recruited. Blood was collected from participants after an overnight fast (baseline) and at 3 and 5 hours after ingestion of a high-fat meal. At each time point, monocyte phenotypes were examined by multiparameter flow cytometry. Main Outcome Measures: Baseline levels of activation markers and postprandial inflammatory response in each of the three monocyte subsets were measured. Results: At baseline, individuals with obesity and MS had higher proportions of circulating lipid-laden foamy monocytes than controls, which were positively correlated with fasting triglyceride levels. Additionally, the MS group had increased counts of nonclassical monocytes, higher CD11c, CX3CR1, and human leukocyte antigen-DR levels on intermediate monocytes, and higher CCR5 and tumor necrosis factor-α levels on classical monocytes in the circulation. Postprandial triglyceride increases in both groups were paralleled by upregulation of lipid-laden foamy monocytes. MS, but not control, subjects had significant postprandial increases of CD11c and percentages of IL-1β+ and tumor necrosis factor-α+ cells in nonclassical monocytes. Conclusions: Compared to controls, individuals with obesity and MS had increased fasting and postprandial monocyte lipid accumulation and activation.

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Lozano, Javier, Dominic C. Chow, Lishomwa C. Ndhlovu, Chathura Siriwardhana, Jocelyn Liu, Jason Irei, Lorna Nagamine, Cecilia Shikuma, and William A. Boisvert. "Functional differences in behavior of monocyte/macrophage from HIV+ patients versus healthy subjects." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 220.23. http://dx.doi.org/10.4049/jimmunol.204.supp.220.23.

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Abstract Increased risk of atherosclerotic cardiovascular diseases is common in HIV+ adults on stable antiretroviral treatment (ART). A key step in the development of the atherosclerotic plaque is the transmigration of monocytes to the plaque area and their differentiation into macrophages and eventually foam cells. The objective of this study was to determine if the propensity of monocytes to transmigrate as well as their ability to take up and efflux cholesterol is affected by HIV infection. Monocytes (transmigration) and differentiated macrophages (lipid metabolism) from HIV+ ART treated patients were compared against those from matched controls as a single point cross-sectional study. Monocyte transmigration was assessed by transwell assay using MCP1 as a chemoattractant, whereas lipid uptake was measured by flow cytometry analysis of internalized acetylated LDL and cholesterol efflux by tracking tritiated cholesterol excreted from the cell after exposure to HDL. Interestingly, isolation of monocytes via negative selection with magnetic beads revealed that the yield of monocyte was significantly lower from HIV+ patients compared to controls. While no significant differences were found in cholesterol uptake or efflux parameter, the ability of monocyte to transmigrate was slightly increased in HIV patients compared to controls suggesting that the chemotactic function of monocytes may be partly responsible for the differences in the atherosclerosis risk in patients with HIV.

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Tabe, Yoko, Shinichi Yamamoto, Mika Kikkawa, Hikari Taka, Kaoru Mogushi, Hiromichi Mastushita, Takashi Miida, Michael Andreeff, Paul A. Spagnuolo, and Marina Konopleva. "Novel FAO Inhibitor Avocatin B Induces Apoptosis of Acute Monocytic Leukemia Cells in Adipocyte Co-Culture System Via ER Stress and ATF4 Activation." Blood 126, no. 23 (December 3, 2015): 3692. http://dx.doi.org/10.1182/blood.v126.23.3692.3692.

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Abstract Adipocytes are the prevalent stromal cell type in aged adult bone marrows (BM). We previously demonstrated prominent pro-survival role of BM-derived adipocytes for the acute monocytic leukemia (AMoL) cells, a poor-prognosis subtype of AML (Tabe ASH. 2013). A novel anticancer agent avocatin B, an odd-numbered carbon lipid derived from avocado fruit, has been shown to induce leukemia cell death by inhibiting fatty acid oxidation (FAO) via its accumulation in mitochondria (Lee, Cancer Res. 2015). In this study, we investigated the cytotoxic efficacy and molecular mechanisms of avocatin B in AMoL cells co-cultured with BM-derived adipocytes, mimicking the aging BM microenvironment. AMoL cell lines (THP1, MOLM13 and U937) and mesenchymal stem cells (MSC)-derived adipocytes were used for this study. Adipocytes inhibited spontaneous apoptosis in AMoL cells, consistent with our prior observations. Avocatin B successfully induced apoptosis and cell growth inhibition in AMoL cells (IC50s between 15 and 73uM) with G0/G1 cell cycle accumulation. We further observed that avocatin B synergistically enhanced AraC induced apoptosis in AMoL cells cultured alone or co-cultured with adipocytes (Figure 1). To this end, avocatin B synergized with Ara C with combination index value of 0.15. Immunoblot analysis demonstrated that avocatin B inactivated the stress response kinase phospho- (p-) AMPK and p-p38 MAPK in MOLM13 co-cultured with adipocytes but not in AML cells cultured alone. These results indicate that avocatin B disrupted the energy homeostasis under adipocyte co-culture condition. Metabolic profiling using the capillary electrophoresis mass spectrometry (CE-MS) detected alteration of 12 polar metabolites (fold change > 2, P<0.05) in THP1 cells after adipocyte co-culture, including downregulation of Glucose 6-phosphate and Fructose 6-phosphate, and upregulation of citric acid, fumaric acid, malic acid and NAD+, which is consistent with AMPK signaling activation and suggests the downregulation of glycolysis and the compensatory activation of oxidative phosphorylation and FAO. To further characterize the molecular mechanisms of pro-apoptotic effects of avocatin B, we focused on the gene transcriptional modulation induced by avocatin B in adipocyte co-cultures. We previously reported that CPT1(carnitine palmitoyltransferase I), a key enzyme of FAO, induced mitochondrial accumulation of avocatin B which resulted in AML cell apoptosis (Lee, Cancer Res. 2015). By RT-PCR analysis, we observed that avocatin B itself induced CPT1 (carnitine palmitoyltransferase I) mRNA. In addition, adipocyte co-culture upregulated FABP4 (fatty acid binding protein 4)which was further increased by avocatin B treatment in THP1, U937 and MOLM13 cells. These findings likely reflect the direct feedback of FAO inhibition by avocatin B. DNA microarray (Affymetrix) detected the upregulation of 45 genes and downregulation of 58 genes in THP1 cells after co-culture with adipocytes (> 2.0 fold). Ingenuity Pathway Analysis (IPA) and KEGG bioinformatics tools highlighted the cytokine-cytokine receptor interaction as the top upregulated pathway with the potent upstream regulators CXCL12, STAT3, p38 MAPK and NFkB activation. In turn, avocatin B treatment upregulated 71 genes and downregulated 27 genes in THP1 cells co-cultured with adipocytes. Among induced genes, avocatin B treatment caused upregulation of the stress response genes DDIT4, SESN2, PCK2, PHGDH, PSAT1 and STC2 that are the downstream targets of transcription factor ATF4, the master regulator of the endoplasmic reticulum (ER) stress response. In summary, the avocatin B and AraC combination induced significant leukemia cell death under adipocyte co-culture conditions. Metabolome and transcriptome analyses indicate that FAO inhibition by avocatin B induced ER stress might stimulate the DDIT3/CHOP-dependent cell death via transcriptional activation of ATF4 (Figure 2). We conclude that the strategies targeting FAO warrant further exploration in patients with AMMoL, highly dependent on altered lipid metabolism. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

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ROSAS-BALLINA, MAURICIO, Xue Li Guan, Nura Schürmann, Alexander Schmidt, and Dirk Bumann. "Mechanism of lipid droplet accumulation in mononuclear phagocytes during sepsis (IRM9P.461)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 130.6. http://dx.doi.org/10.4049/jimmunol.194.supp.130.6.

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Abstract Lipid droplet formation in phagocytes is associated with various important inflammatory conditions, and their accumulation modulates disease progression. We used proteomics, lipidomics, and cell bioenergetics experiments to unravel the metabolic basis of lipid droplet accumulation in a murine model of Salmonella infection. Lipid droplets accumulated in inflammatory monocytes and neutrophils within spleen inflammatory lesions, and this is recapitulated in vitro by treating monocytes with the pro-inflammatory cytokine IFNγ. Bioenergetic experiments suggested that iNOS-derived nitric oxide blocks the mitochondrial electron transport chain thus inhibiting respiration and oxidation of fatty acids, which instead accumulate within lipid droplets. Surprisingly, metabolite tracing with 13C-labeled substrates revealed that de novo synthesis of fatty acid from glutamine or glucose plays no major role in lipid accumulation, in stark contrast to the otherwise similar metabolism of cancer cells. Instead, the glycerol head group in triacylglycerol and phospholipid entirely derives from glucose, while the fatty acid carbons originate from uptake of external lipids. Our results identify neutrophils and inflammatory monocytes as a depot of neutral lipid during infection, and establish remodeling of imported lipids with exchange of head groups for newly synthesized glycerol as the underlying metabolic mechanism of lipid droplet accumulation upon activation with IFNγ.

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Taghizadeh, Eskandar, Forough Taheri, Pedram G. Renani, Željko Reiner, Jamshid G. Navashenaq, and Amirhossein Sahebkar. "Macrophage: A Key Therapeutic Target in Atherosclerosis?" Current Pharmaceutical Design 25, no. 29 (October 21, 2019): 3165–74. http://dx.doi.org/10.2174/1381612825666190830153056.

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Background: Atherosclerosis is a chronic inflammatory disease and a leading cause of coronary artery disease, peripheral vascular disease and stroke. Lipid-laden macrophages are derived from circulating monocytes and form fatty streaks as the first step of atherogenesis. Methods: An electronic search in major databases was performed to review new therapeutic opportunities for influencing the inflammatory component of atherosclerosis based on monocytes/macrophages targeting. Results: In the past two decades, macrophages have been recognized as the main players in atherogenesis but also in its thrombotic complications. There is a growing interest in immunometabolism and recent studies on metabolism of macrophages have created new therapeutic options to treat atherosclerosis. Targeting recruitment, polarization, cytokine profile extracellular matrix remodeling, cholesterol metabolism, oxidative stress, inflammatory activity and non-coding RNAs of monocyte/macrophage have been proposed as potential therapeutic approaches against atherosclerosis. Conclusion: Monocytes/macrophages have a crucial role in progression and pathogenesis of atherosclerosis. Therefore, targeting monocyte/macrophage therapy in order to achieve anti-inflammatory effects might be a good option for prevention of atherosclerosis.

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Christofides, Anthos, Carol Cao, Qi Wang, Natalia M. Tijaro-Ovalle, Eirini Konstantinidou, Rushil Shah, Chinmay Jani, et al. "Pparα Ablation Suppresses T Cell Responses and Anti-Tumor Immunity By Compromising the Antigen-Presenting Properties of Tumor-Associated Macrophages." Blood 138, Supplement 1 (November 5, 2021): 438. http://dx.doi.org/10.1182/blood-2021-149071.

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Abstract Peroxisome proliferator activated receptors (PPARs) are transcription factors that belong to nuclear hormone superfamily, with three distinct types identified: PPARapha (PPARα), PPARgamma (PPARγ), and PPARbeta/delta (PPARβ/δ). PPARs possess a critical role in the regulation of lipid metabolism, and thus play critical roles in the differentiation and fate of immune cells. PPARα is involved in lipid and carbohydrate metabolism and PPARα agonists, such as fibrates, have been used for the treatment of hypertriglyceridemia and cardiovascular diseases. PPARα has an anti-inflammatory role during infection, and similar to PPARγ, affects the polarization of macrophages. In acute myelogenous leukemia (AML), PPARα mutations correlate with chemoresistance, poor treatment outcomes and unfavorable prognosis. In experimental tumor models, it has been proposed that PPARα agonists might enhance anti-tumor T cell responses during PD-1 blocking immunotherapy. To dissect the mechanistic role of PPARα in tumor immunity, we used mice with global deletion of PPARα and examined tumor growth and profile of the immunological landscape, using various syngeneic tumor models. Significantly larger B16-F10 melanoma and MC-17 fibrosarcoma tumors were observed in PPARα KO mice compared with wild-type control, suggesting that PPARα deletion attenuated the immunological response against cancer. To dissect the role of PPARα in key populations of the innate and adaptive immune system involved in anti-tumor responses, we analyzed the immunological landscape of tumor, tumor draining lymph nodes (TDLN) and spleen, 14-16 days after tumor implantation. Assessment of CD4 + and CD8 + T cells, CD11b +F4/80 + tumor-associated macrophages (TAMs), CD11b +Ly6C hiLy6G - monocytic myeloid derived suppressor cells (M-MDSC), and CD11b +Ly6C loLy6G + polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), by using flow cytometry, showed no quantitative differences between the two experimental groups. Functionally, MDSC from PPARα KO and WT mice showed comparable immunosuppressive properties as determined by suppression assay using splenocytes from OTI transgenic mice. However, PPARα KO TAMs demonstrated a less activated state, as determined by the lower expression levels of MHC-II that is critical for antigen presentation, and CD86 that is critical for T cell costimulation and prevention of T cell anergy and exhaustion. In agreement with these properties of TAMs, CD4 + T cells from TDLN of PPARα KO mice had diminished expression of activation markers, including PD-1, PD-L1 and ICOS, and numerically decreased central memory-like CD4 + T cells (T CM), compared to control tumor bearing mice. Furthermore, CD69, an emerging marker of T cell exhaustion, was significantly upregulated in CD4 + and CD8 + T cells from the TDLN of PPARα KO mice. To determine whether PPARα ablation altered the cell intrinsic properties of myeloid cells and/or T cells resulting in impaired anti-tumor function, we examined in vitro responses of isolated populations. In response to activation via TCR/CD3 and CD28, PPARα deficient T cells had no significant differences in expansion and cytokine production compared to control. In contrast, PPARα deficient Ly6C + monocytes isolated from the bone marrow displayed diminished responses to TLR-mediated signaling as determined by production of IL-6 and TNFα. Our in vitro and in vivo findings reveal a dominant role of PPARα in regulating the fate of innate immune cells thereby altering T cell responses and anti-tumor function. Our findings have implications for the development of new therapeutic approaches to enhance innate immune cell function for the improvement of cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

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Guo, Zhigang, Lixue Wang, Hongjian Liu, and Yuhuai Xie. "Innate Immune Memory in Monocytes and Macrophages: The Potential Therapeutic Strategies for Atherosclerosis." Cells 11, no. 24 (December 15, 2022): 4072. http://dx.doi.org/10.3390/cells11244072.

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Atherosclerosis is a complex metabolic disease characterized by the dysfunction of lipid metabolism and chronic inflammation in the intimal space of the vessel. As the most abundant innate immune cells, monocyte-derived macrophages play a pivotal role in the inflammatory response, cholesterol metabolism, and foam cell formation. In recent decades, it has been demonstrated that monocytes and macrophages can establish innate immune memory (also termed trained immunity) via endogenous and exogenous atherogenic stimuli and exhibit a long-lasting proinflammatory phenotype. The important cellular metabolism processes, including glycolysis, oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and cholesterol synthesis, are reprogrammed. Trained monocytes/macrophages with innate immune memory can be persistently hyperactivated and can undergo extensive epigenetic rewiring, which contributes to the pathophysiological development of atherosclerosis via increased proinflammatory cytokine production and lipid accumulation. Here, we provide an overview of the regulation of cellular metabolic processes and epigenetic modifications of innate immune memory in monocytes/macrophages as well as the potential endogenous and exogenous stimulations involved in the progression of atherosclerosis that have been reported recently. These elucidations might be beneficial for further understanding innate immune memory and the development of therapeutic strategies for inflammatory diseases and atherosclerosis.

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de Metz, Jesse, Johannes A. Romijn, Erik Endert, Mariette T. Ackermans, Gerrit Jan Weverling, Olivier R. Busch, Laurence Th de Wit, Dirk J. Gouma, Ineke J. M. ten Berge, and Hans P. Sauerwein. "Interferon-γ increases monocyte HLA-DR expression without effects on glucose and fat metabolism in postoperative patients." Journal of Applied Physiology 96, no. 2 (February 2004): 597–603. http://dx.doi.org/10.1152/japplphysiol.00090.2002.

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Tissue injury is associated with decreased cellular immunity and enhanced metabolism. Immunodepression is thought to be counteracted by interferon (IFN)-γ, which increases human leukocyte antigen (HLA)-DR expression. Hypermetabolism could be enhanced by IFN-γ because cytokines induce a hypermetabolic response to stress. In healthy humans, IFN-γ enhanced HLA-DR expression without effects on glucose and fat metabolism. In the present study, we evaluated whether IFN-γ lacks potential harmful side effects on metabolic and endocrine pathways while maintaining its beneficial effects on the immune system under conditions in which the inflammatory response system is activated. In 13 patients scheduled for major surgery, we studied HLA-DR expression on peripheral blood monocytes before surgery and postoperatively randomized the patients into an intervention and a placebo group. Subsequently, we evaluated the effects of a single dose of IFN-γ vs. saline on short-term monocyte activation, glucose and lipid metabolism, and glucose and lipid regulatory hormones. HLA-DR expression on monocytes was restored from postoperative levels of 54% (42-60%; median and interquartiles) to 92% (91-96%) 24 h after IFN-γ adminstration but stayed low in the placebo-treated patients. IFN-γ did not affect glucose metabolism (plasma glucose, rate of appearance and dissappearance of glucose) and lipid metabolism (plasma glycerol, plasma free fatty acids, and rates of appearance and disappearance of glycerol). IFN-γ had no effect on plasma cortisol, adrenocorticotropic hormone, growth hormone, insulin, C-peptide, glucagon, epinephrine, and norepinephrine concentrations. We conclude that IFN-γ exerts a favorable effect on cell-mediated immunity in patients after major surgery without effects on glucose and lipid metabolism.

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Watschinger, Katrin, Markus A. Keller, Eileen McNeill, Mohammad T. Alam, Steven Lai, Sabrina Sailer, Veronika Rauch, et al. "Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome." Proceedings of the National Academy of Sciences 112, no. 8 (February 9, 2015): 2431–36. http://dx.doi.org/10.1073/pnas.1414887112.

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Tetrahydrobiopterin is a cofactor synthesized from GTP with well-known roles in enzymatic nitric oxide synthesis and aromatic amino acid hydroxylation. It is used to treat mild forms of phenylketonuria. Less is known about the role of tetrahydrobiopterin in lipid metabolism, although it is essential for irreversible ether lipid cleavage by alkylglycerol monooxygenase. Here we found intracellular alkylglycerol monooxygenase activity to be an important regulator of alkylglycerol metabolism in intact murine RAW264.7 macrophage-like cells. Alkylglycerol monooxygenase was expressed and active also in primary mouse bone marrow-derived monocytes and “alternatively activated” M2 macrophages obtained by interleukin 4 treatment, but almost missing in M1 macrophages obtained by IFN-γ and lipopolysaccharide treatment. The cellular lipidome of RAW264.7 was markedly changed in a parallel way by modulation of alkylglycerol monooxygenase expression and of tetrahydrobiopterin biosynthesis affecting not only various ether lipid species upstream of alkylglycerol monooxygenase but also other more complex lipids including glycosylated ceramides and cardiolipins, which have no direct connection to ether lipid pathways. Alkylglycerol monooxygenase activity manipulation modulated the IFN-γ/lipopolysaccharide–induced expression of inducible nitric oxide synthase, interleukin-1β, and interleukin 1 receptor antagonist but not transforming growth factor β1, suggesting that alkylglycerol monooxygenase activity affects IFN-γ/lipopolysaccharide signaling. Our results demonstrate a central role of tetrahydrobiopterin and alkylglycerol monooxygenase in ether lipid metabolism of murine macrophages and reveal that alteration of alkylglycerol monooxygenase activity has a profound impact on the lipidome also beyond the class of ether lipids.

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Sanders, Stephanie, Denise Herpai, Lance Miller, and Waldemar Debinski. "TMIC-36. ALDH1A2 AS A NOVEL PUTATIVE MARKER OF MACROPHAGE DIFFERENTIATION IN GBM." Neuro-Oncology 21, Supplement_6 (November 2019): vi255. http://dx.doi.org/10.1093/neuonc/noz175.1070.

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Abstract Tumor-associated macrophages (TAM) are abundant in glioblastoma (GBM), composing up to 30% of the total tumor mass. However, their genotype/phenotype and exact role in tumor progression and immune suppression are not fully understood. Macrophages are believed to be polarized along a spectrum spanning from M0, M1, and M2 states. M1 TAMs are proinflammatory while M2 TAMs are associated with anti-inflammatory, pro-tumor responses. For example, using gelatin zymography we saw an increase in MMP 2 and 9 activities in co-culture of GBM cells and M2 polarized macrophages. In search for factors determining M2 type TAMs, we found Aldehyde Dehydrogenase 1 family A2 (ALDH1A2) to be highly over-expressed in M2 polarized THP1 cells using a gene expression array. We also performed single cell sequencing on CD45+ cells isolated from GBM tumors using antibody-conjugated magnetic beads. Monocytic/macrophage cells were found in 2 clusters and ALDH1A2 expression was increased in 2.1% of CD68+/CD163+ cells in Cluster 1 and 2.7% of CD68+/CD163+ cells in Cluster 2. Notably, ALDH1A2 was not detected in peripheral blood mononuclear cells. Analysis of the single cell sequencing data has led to identification of several genes whose expression is increased in ALDH1A2+ cells compared to ALDH1A2- cells. These genes are associated with lipid metabolism, regulation of neoplastic transformation, and insulin growth factor signaling. To further validate these results, we co-stained GBM tumor sections for CD163 and ALDH1A2 and observed that ALDH1A2 is co-localized in M2 macrophages. We have noticed a propensity of ALDH1A2+ cells to be associated with tumor neovasculature. Being that ALDH1A2 is the main enzyme in retinoic acid (RA) synthesis, it is plausible that this could represent another possible function of these enzyme-positive TAMs. Taken together these data suggest a role for ALDH1A2 as a novel putative marker of a subset of M2 TAM phenotype and function in GBM.

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Andersen, Catherine, and Terrence Vance. "Gender Dictates the Relationship between Serum Lipids and Leukocyte Counts in the National Health and Nutrition Examination Survey 1999–2004." Journal of Clinical Medicine 8, no. 3 (March 15, 2019): 365. http://dx.doi.org/10.3390/jcm8030365.

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Dyslipidemias and leukocytosis are associated with cardiovascular disease and immune disorders. Mechanistic studies have shown lipoprotein metabolism to play a significant role in the regulation of atherosclerosis development and leukocyte activation, whereas lipid-lowering treatments have been shown to exert beneficial anti-inflammatory and immunomodulatory effects in clinical trials. However, the relationship between clinical markers of lipid metabolism and leukocyte counts has not been extensively evaluated at the population level. We aimed to determine whether clinical blood lipid measures are associated with leukocyte counts in the general U.S. population represented in the National Health and Nutrition Examination Survey (NHANES) 1999–2004, and whether differences exist between men and women (n = 5647). We observed a strong positive linear trend between serum triglycerides vs. blood lymphocyte and basophil counts in both men and women, whereas a positive trend between monocytes vs. triglycerides and lymphocytes vs. total cholesterol and LDL-cholesterol (LDL-C) was only detected in women. Conversely, HDL-C was inversely associated with a greater number of leukocyte subsets in men, whereas inverse trends between HDL-C vs. lymphocytes were observed in both men and women. In multiple regression models, a 10% increase in total cholesterol, LDL-C, and triglycerides was associated with a predicted 1.6%, 0.6%, and 1.4% increase in blood lymphocyte counts in women, respectively, whereas no relationship was observed in men. In both men and women, a 10% increase in triglycerides was additionally associated with higher lymphocyte, neutrophil, and basophil counts, whereas 10% increases in HDL-cholesterol were associated with significantly lower lymphocyte, neutrophil, eosinophil, and basophil counts in men, in addition to lower lymphocyte and monocyte counts in women. These findings suggest that clinical lipid markers may be used to predict blood leukocyte distributions, and that a gender-specific relationship exists between distinct classes of serum lipids and immune cell subsets.

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Cerqueira, Bruno A. V., Wendell Vilas-Boas, Jose Moura Neto, Jorge Clarencio, Daniela Andrade, Rodrigo Cezar, Angela Zanette, Mitermayer Reis, and Marilda Goncalves. "CD32, CD18, CD11b and CD62L Expression on Monocyte without and After Lipopolysaccharide (LPS) Challenge: Association with Inflammatory and Hemolysis Markers In Sickle Cell Anemia." Blood 116, no. 21 (November 19, 2010): 1655. http://dx.doi.org/10.1182/blood.v116.21.1655.1655.

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Abstract Abstract 1655 Introduction: Vaso-occlusive episodes (VOE) in sickle cell anemia, homozygous form of hemoglobin S (HB S), involve interactions between sickle red blood cells (RBC), endothelial cells, leukocytes, platelets, coagulation factors and plasma proteins. The purpose of the present study was explore the inflammatory potential of monocytes, activation state, response against challenge and its association with hemolytic, inflammatory, lipid metabolism and medical history of SCA patients. Patients and Methods: We studied 27 SCA patients in steady-state (11 men, 16 women, mean age: 22.26 ± 16.03 years) from Northeast Brazil diagnosed with SCA in attendance of the outpatients clinic of the Foundation of Hematology and Hemotherapy of Bahia (HEMOBA). The control group was compound by 20 healthy Brazilian, with AA hemoglobin pattern matched by age, years and ethnic origin. The study was approved by the FIOCRUZ ethical committee and informed consents were signed by patients or official responsible. The lipid and hemolytic profile were measured by biochemical colorimetric methods, hematological analysis and hemoglobin profile were performed using an electronic cell counter and HPLC, respectively, cytokines and surface molecules expressions on monocytes were evaluated by flow cytometry (labeled with monoclonal anti-CD11b, anti-CD18, ant-CD32, anti-CD62L and anti-HumanTNF), the monocyte activation was stimulated by LPS and the complete medical history was obtained by patients' record. Results: Our results show higher CD11b monocyte expression in SCA patients than control group (p=0.000) and lower CD18 and CD32 on monocyte expression in SCA patients than control group (p=0.001; p=0.018). After LPS stimulation, we observed increased expression of CD11b, CD18 and CD32 expression on monocyte in SCA (p=0.000) so as in the control group (p=0.000). Moreover, monocyte expression of CD32 was negatively associated with aspartate aminotransferase (r=-0.468; p=0.014) and hemoglobin S (r=-0.389; p=0.045), but presented positive correlation with TNF-alpha (r=0.414; p=0.044). In another hand, the monocyte expression of CD62L was associated with an increase of hemoglobin concentration (r=0.496; p=0.009) and high density lipoprotein-cholesterol (r=0.505; p=0.007). Sickle cell anemia individuals that developed splenic sequestration exhibited increased expression of CD11b on monocyte surface. Conclusion: The study of monocyte surface molecule and its association with markers of hemolysis, inflammation and lipid metabolism may indicate a differentiated mechanism of these molecules in sickle cell anemia pathogenesis, with a complex involvement of cellular, endothelial and proinflammatory interactions. Additional studies should be carried out in order to explore the contribution of monocyte expression surface molecule on vascular occlusion in the sickle cell anemia. Disclosures: No relevant conflicts of interest to declare.

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Ysebaert, Loic, Mary Poupot, Yovan Sanchez-Ruiz, Camille Laurent, Guy Laurent, and Jean-Jacques Fournié. "Chronic Lymphocytic Leukemia-Associated Macrophages: Not Just Nurse Cells." Blood 116, no. 21 (November 19, 2010): 46. http://dx.doi.org/10.1182/blood.v116.21.46.46.

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Abstract Abstract 46 Introduction: CLL cells interact with many accessory cells in an environment mimicking that of normal mature B cells. Role of antigen, cytokines, adhesion pathways are critical for many aspects in the disease course (proliferation/survival, migration or homing, drug resistance, and presumably relapse). Nurse-like cells (NLC) belong to a monocytic-derived, bystander population among CLL lymph node and spleen stromal cells. Aim: To investigate the nature, functions, and location of NLC within CLL microenvironment. Methods: Gene expression profiles (GEP) from in vitro expanded NLC from patients (n=10) were produced and compared to those from normal CD14+ monocytes, M1-polarized macrophages, M2-polarized macrophages and tumor-associated macrophages (produced in the lab or downloaded from GEO datasets). Principal Component Analysis was used to categorize these five populations of cells and in-house-built GSEA software was used for functional interpretation of their relevant gene lists. Protein expression patterns were validated with multi-analyte ELISArray kits, proteome profiler arrays, flow cytometry (FC) or immunohistochemistry (IHC). Results: New insights into the physiopathological role of NLC in CLL are suggested from five lines of evidence: 1/a Òmonocytic gene signatureÓ (i.e. a set of 549 genes) is shared by the NLC and the monocyte subtypes. The genes over-represented in NLC vs normal monocytes pinpointed positive modulation of apoptotic cell clearance (scavenger, mannose and complement receptors, LXRalpha), lipid metabolism (Apolipoprotein E, PPAR signaling), extracellular matrix-receptor interactions (integrins, SPARC, Matrix MetalloProteinases) and actin cytoskeleton remodeling. 2/unsupervised clustering show that NLC represent an M2-skewed, TAM-like cell population. They down-regulate mRNA and proteins for classic M1 inflammatory markers (e.g. IL-1, IL-6, IL-12, COX2) while increase secretion of TGFbeta, IL-10, CCL17 and CCL22 soluble factors. 3/these and previously published observations suggest that B-CLL-to-NLC interactions may orchestrate immunosuppression in this disease. PBMCs from Òwatch and waitÓ CLL patients (all stage A/Rai 0, mutated IgVH, low risk cytogenetics profile) or healthy donors were stimulated with anti-CD3/CD28 beads + IL-2, either in standard RPMI+10% FCS or in conditioned medium (CM, after 14d CLL-NLC co-culture in vitro) and their proliferation/phenotype were compared after 2 weeks. Significant expansion of T cells with Treg (CD4+CD25+FoxP3+) phenotype was observed only from CLL PBMCs grown in conditioned medium (mean % Treg: 2.85 vs 3.05 in CM for normal PBMCs, and 1.54 vs 15.9 in CM for CLL PBMCs, P< 0.05). 4/although NLC make immune synapses with live B-CLL, they do not phagocytose them. Over-expression of CD47 (ÒdonÕt eat meÓ signal) by B-CLL cells (mfi= 3490 vs 2581 on normal cells, P< 0.05, n=18) may provide them with a protective signal against NLC. 5/from our GEP, flow cytometric and IHC analyses, we propose CD163 (classic M2 marker) as a reliable tool to identify NLC in vivo. Although in vitro, CLL cells can pervert healthy donor monocytes into NLC, only CLL-derived NLC are truly CD14+ CD163+. In vivo, CD163 staining reveals putative NLC in CLL lymph nodes(LN)/spleen sections but not in bone marrow. In LN from all patients, NLC reside in the subcapsular areas and line vessel structures, suggesting a role in CLL cells trafficking. Most interestingly, NLC infiltrate pseudofollicles structures only in a subset of cases. We will present updated IHC and clinical presentation correlation studies. Conclusions: Our results suggest that the role of NLC in CLL might be broader than initially thought. Beside of nursing and conferring drug resistance, NLC may also be crucial in the setting of immunosuppression, of CLL cells recruitment, and should thus be considered as therapeutic targets. Disclosures: Off Label Use: GA101 is not currently approved for CLL treatment.

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Furlong, Stephen T., Alma Mednis, and Heinz G. Remold. "Interferon-γ stimulates lipid metabolism in human monocytes." Cellular Immunology 143, no. 1 (August 1992): 108–17. http://dx.doi.org/10.1016/0008-8749(92)90009-e.

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Hashimoto, Shin-ichi, Takuji Suzuki, Hong-Yan Dong, Nobuyuki Yamazaki, and Kouji Matsushima. "Serial Analysis of Gene Expression in Human Monocytes and Macrophages." Blood 94, no. 3 (August 1, 1999): 837–44. http://dx.doi.org/10.1182/blood.v94.3.837.413k02_837_844.

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Monocytes/macrophages serve as sentinels involved in chronic inflammation and the eradication of various pathogens. To define molecularly the differentiation of blood monocytes into macrophages, we conducted serial analysis of gene expression (SAGE) in human blood monocytes/macrophages induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) or M-CSF. SAGE analysis of 57,560, 57,463, and 55,856 tags from monocytes, GM-CSF–, and M-CSF–induced macrophages, respectively, allowed identification of 35,037 different transcripts. Interestingly, the genes with the highest expression during differentiation from monocytes into macrophages were genes involved in lipid metabolism. Both CSF-induced macrophages expressed similar sets of genes except for several genes such as monocyte-derived chemokine (MDC), legumain, prostaglandin D synthetase, and lysosomal sialoglycoprotein. The identification of specific gene expression in human monocytes, GM-CSF–, or M-CSF–induced macrophages provides novel methods to define macrophage subsets and the maturation and activation stage of cells of macrophage lineage and, possibly, to diagnose diseases in which macrophages play a major role. This study represents the first extensive serial analysis of gene expression for any type of human hematopoietic cells.

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Mingione, Alessandra, Emerenziana Ottaviano, Matteo Barcella, Ivan Merelli, Lorenzo Rosso, Tatiana Armeni, Natalia Cirilli, Riccardo Ghidoni, Elisa Borghi, and Paola Signorelli. "Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism." Cells 9, no. 8 (August 6, 2020): 1845. http://dx.doi.org/10.3390/cells9081845.

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Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients’ derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients’ monocytes killing of A. fumigatus. CF patients’ monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes.

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Vangaveti, Venkat, Venkatesh Shashidhar, Fiona Collier, Jason Hodge, Catherine Rush, Usman Malabu, Bernhard Baune, and Richard Lee Kennedy. "9- and 13-HODE regulate fatty acid binding protein-4 in human macrophages, but does not involve HODE/GPR132 axis in PPAR-γ regulation of FABP4." Therapeutic Advances in Endocrinology and Metabolism 9, no. 5 (February 27, 2018): 137–50. http://dx.doi.org/10.1177/2042018818759894.

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Background: Both activation of monocytes and increased serum fatty acid binding protein-4 (FABP4) occur in diabetes and are associated with increased atherosclerosis. The oxidized lipid, 9-hydroxyoctadecadienoic acid (9-HODE) increases FABP4 in macrophages, and is a ligand for G protein-coupled receptor 132 (GPR132). We investigated the involvement of GPR132 in mediating the 9-, 13-HODE stimulation of FABP4 secretion, and whether GPR132 expression is increased in monocytes from patients with type 2 diabetes. Methods: The effects of siRNA silencing of GPR132 gene and of the PPAR-γ antagonist T0070907 were studied in THP-1 cells. Serum levels of FABP4 and other adipokines were measured in patients with diabetes, and monocyte subpopulations were analyzed using flow cytometry. GPR132 mRNA was quantified in isolated CD14+ cells. Results: 9-HODE and 13-HODE increased FABP4 expression in THP-1 monocytes and macrophages, and also increased GPR132 expression. Silencing of GPR132 did not influence the increase in FABP4 with 9-HODE, 13-HODE, or rosiglitazone (ROSI). By contrast, T0070907 inhibited the effect of all three ligands on FABP4 expression. Diabetic subjects had increased serum FABP4, and activated monocytes. They also expressed higher levels of GPR132 mRNA in CD14+ cells. Conclusions: We conclude that GPR132 is an independent monocyte activation marker in diabetes, but does not contribute to PPAR-γ-mediated induction of FABP4 by HODEs.

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Falero-Diaz, Gustavo, Catarina de A. Barboza, Felipe Pires, Maeva Fanchin, Jingjing Ling, Zachary M. Zigmond, Anthony J. Griswold, et al. "Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 2 (February 2022): 175–88. http://dx.doi.org/10.1161/atvbaha.121.317197.

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Objective: Monocytes, which play an important role in arteriogenesis, can build immunologic memory by a functional reprogramming that modifies their response to a second challenge. This process, called trained immunity, is evoked by insults that shift monocyte metabolism, increasing HIF (hypoxia-inducible factor)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. Methods and Results: Mice exposed to ischemia by 24 hours (24h) of femoral artery occlusion (24h trained) or sham were subjected to hindlimb ischemia one week later; the 24h trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24h trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24h ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 (glucose transporter-1) gene expression during femoral artery occlusion. Circulating cytokines and GLUT-1 were also upregulated during femoral artery occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24h trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, 4 were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24h hypoxia. Conclusions: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.

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Schmitz, G., H. Fischer, M. Beuck, K. P. Hoecker, and H. Robenek. "Dysregulation of lipid metabolism in Tangier monocyte-derived macrophages." Arteriosclerosis: An Official Journal of the American Heart Association, Inc. 10, no. 6 (November 1990): 1010–19. http://dx.doi.org/10.1161/01.atv.10.6.1010.

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Olivieri, Oliviero, Sara Gasperini, Federica Calzetti, Elisa Gardiman, Annalisa Castagna, Nicola Martinelli, Nicola Tamassia, and Marco A. Cassatella. "CD14+-Monocytes Exposed to Apolipoprotein CIII Express Tissue Factor." International Journal of Molecular Sciences 24, no. 3 (January 22, 2023): 2223. http://dx.doi.org/10.3390/ijms24032223.

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Apolipoprotein CIII (ApoCIII) represents a key regulator of plasma lipid metabolism and a recognized risk factor for atherosclerosis and cardiovascular diseases. Beyond the regulation of lipoprotein trafficking, ApoCIII is also involved in endothelial dysfunction and monocyte recruitment related to atherothrombosis. With tissue factor (TF) being the primary initiator of the blood coagulation cascade, we hypothesized that ApoCIII-treated monocytes could express it. Hence, human CD14+-monocytes and autologous neutrophils were incubated with ApoCIII and sera from human subjects containing previously measured ApoCIII amounts. By RT-qPCR and ELISA, CD14+-monocytes, but not neutrophils, were found to show increased mRNA expression and production of TNFα, IL-1β and IL-6 as well as TF mRNA once exposed to ultra-purified ApoCIII. By flow cytometry, CD14+-monocytes were found to rapidly express TF on their cell surface membrane when incubated with either ApoCIII or sera with known concentrations of ApoCIII. Finally, preincubation with specific ApoCIII-neutralizing antibodies significantly reduced the ability of most sera with known concentrations of ApoCIII to upregulate TF protein, other than partially inhibiting cytokine release, in CD14+-monocytes. In sum, herein we demonstrate that ApoCIII activates CD14+-monocytes to express TF. The data identify a potential mechanism which links circulating apolipoproteins with inflammation and atherothrombosis-related processes underlying cardiovascular risk.

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Wharton, David, Nima Gharavi, Mohamad Navab, Sangderk Lee, Judith Berliner, Alan Fogelman, and Robert Modlin. "Role of host lipid metabolism and tissue macrophages in psoriasis (147.30)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 147.30. http://dx.doi.org/10.4049/jimmunol.186.supp.147.30.

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Abstract Epidemiologic studies and clinical co-morbidity suggests a link between psoriasis and atherosclerosis. These conditions share common inflammatory mediators, including macrophage (Mp) signaling and the presence of oxidized low-density lipoprotein (LDL). We examined the role of lipid metabolism and tissue Mp in psoriasis. Using immunohistochemistry on psoriatic tissue, we identified a subpopulation of CD209+/CD163+ dermal Mp which have phagocytic properties and are capable of engulfing oxidized lipids. Next, using gene-expression arrays, we examined the effect of oxidized lipids on Mp signaling. Treatment of THP-1 Mp with a component of minimally oxidized LDL induced the expression of interleukins-1, -6, -15, -17, -23, cathelicidin and vascular endothelial growth factor, all of which play a role is psoriasis. Lastly, we examined the properties of high-density lipoprotein (HDL) in serum from psoriatic patients. In healthy patients, HDL is capable of reverse cholesterol transport and has potent anti-inflammatory properties. In patients with systemic inflammatory disease, including atherosclerosis, HDL loses these properties and becomes dysfunctional. Using a well-established model of monocyte chemotaxis as well as an in-vitro model of IL-23 production, both as markers of inflammation, we demonstrated that HDL from psoriatic patients was dysfunctional and had pro-inflammatory properties. Taken together, these data provide a role for tissue Mp and host lipid metabolism in psoriasis

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Bermúdez, Miguel A., María A. Balboa, and Jesús Balsinde. "Lipid Droplets, Phospholipase A2, Arachidonic Acid, and Atherosclerosis." Biomedicines 9, no. 12 (December 13, 2021): 1891. http://dx.doi.org/10.3390/biomedicines9121891.

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Lipid droplets, classically regarded as static storage organelles, are currently considered as dynamic structures involved in key processes of lipid metabolism, cellular homeostasis and signaling. Studies on the inflammatory state of atherosclerotic plaques suggest that circulating monocytes interact with products released by endothelial cells and may acquire a foamy phenotype before crossing the endothelial barrier and differentiating into macrophages. One such compound released in significant amounts into the bloodstream is arachidonic acid, the common precursor of eicosanoids, and a potent inducer of neutral lipid synthesis and lipid droplet formation in circulating monocytes. Members of the family of phospholipase A2, which hydrolyze the fatty acid present at the sn-2 position of phospholipids, have recently emerged as key controllers of lipid droplet homeostasis, regulating their formation and the availability of fatty acids for lipid mediator production. In this paper we discuss recent findings related to lipid droplet dynamics in immune cells and the ways these organelles are involved in regulating arachidonic acid availability and metabolism in the context of atherosclerosis.

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Menzner, Ann-Katrin, Tanja Rottmar, Simon Voelkl, Jacobus J. Bosch, Dimitrios Mougiakakos, Andreas Mackensen, and Yazid J. Resheq. "Hydrogen-Peroxide Synthesis and LDL-Uptake Controls Immunosuppressive Properties in Monocyte-Derived Dendritic Cells." Cancers 13, no. 3 (January 26, 2021): 461. http://dx.doi.org/10.3390/cancers13030461.

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Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H2O2) depletion. However, the effects on monocyte-derived dendritic cells (moDCs) are unknown. Methods: Monocytes from healthy donors were differentiated to moDCs in the presence of extracellular enzymatic H2O2-depletion (hereinafter CAT-DCs), and studied phenotypically and functionally. To elucidate the underlying molecular mechanisms, we analyzed H2O2- and LDL-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: CAT-DCs were of an immature DC phenotype, particularly characterized by impaired expression of the costimulatory molecules CD80/86. Moreover, CAT-DCs were able to suppress T-cells using indoleamine 2,3-dioxygenase (IDO), and induced IL10/IL17-secreting T-cells—a subtype reported to exert immunosuppression in acute myeloid leukemia. CAT-DCs also displayed significantly increased NADPH-oxidase-driven H2O2-production, enhancing low-density lipoprotein (LDL)-uptake. Blocking LDL-uptake restored maturation, and attenuated the immunosuppressive properties of CAT-DCs. Discussion: Here, we report a novel axis between H2O2- and LDL-metabolism controlling tolerogenic properties in moDCs. Given that moDCs are pivotal in tumor-rejection, and lipid-accumulation is associated with tumor-immune-escape, LDL-metabolism appears to play an important role in tumor-immunology.

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Gogolak, Peter, Bence Rethi, Istvan Szatmari, Arpad Lanyi, Balazs Dezso, Laszlo Nagy, and Eva Rajnavolgyi. "Differentiation of CD1a− and CD1a+ monocyte-derived dendritic cells is biased by lipid environment and PPARγ." Blood 109, no. 2 (September 12, 2006): 643–52. http://dx.doi.org/10.1182/blood-2006-04-016840.

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Abstract Accumulating data have shown that the microenvironment of dendritic cells modulates subtype differentiation and CD1 expression, but the mechanisms by which exogenous factors confer these effects are poorly understood. Here we describe the dependence of CD1a− monocyte-derived dendritic cell (moDC) development on lipids associated with the expression of peroxisome proliferator-activated receptor–gamma (PPARγ). We also show the consecutive differentiation of immature CD1a−PPARγ+ moDCs to CD1a+PPARγ− cells limited by serum lipoproteins and terminated by proinflammatory cytokines. Immature CD1a− moDCs possess higher internalizing capacity than CD1a+ cells, whereas both activated subtypes have similar migratory potential but differ in their cytokine and chemokine profiles, which translates to distinct T-lymphocyte–polarizing capacities. CD1a+ moDCs stand out by their capability to secrete high amounts of IL-12p70 and CCL1. As lipoproteins skew moDC differentiation toward the generation of CD1a−PPARγ+ cells and inhibit the development of CD1a+PPARγ− cells, we suggest that the uptake of lipids results in endogenous PPARγ agonists that induce a cascade of gene transcription coordinating lipid metabolism, the expression of lipid-presenting CD1 molecules, subtype dichotomy, and function. The presence of CD1a−PPARγ+ and CD1a+PPARγ− DCs in lymph nodes and in pulmonary Langerhans cell histiocytosis confirms the functional relevance of these DC subsets in vivo.

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Moheimani, Fatemeh, Joanne T. M. Tan, Bronwyn E. Brown, Alison K. Heather, David M. van Reyk, and Michael J. Davies. "Effect of Exposure of Human Monocyte-Derived Macrophages to High, versus Normal, Glucose on Subsequent Lipid Accumulation from Glycated and Acetylated Low-Density Lipoproteins." Experimental Diabetes Research 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/851280.

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During atherosclerosis monocyte-derived macrophages accumulate cholesteryl esters from low-density lipoproteins (LDLs) via lectin-like oxidised LDL receptor-1 (LOX-1) and class AI and AII (SR-AI, SR-AII) and class B (SR-BI, CD36) scavenger receptors. Here we examined the hypothesis that hyperglycaemia may modulate receptor expression and hence lipid accumulation in macrophages. Human monocytes were matured into macrophages in 30 versus 5 mM glucose and receptor expression and lipid accumulation quantified. High glucose elevated LOX1 mRNA, but decreased SR-AI, SR-BI, LDLR, and CD36 mRNA. SR-BI and CD36 protein levels were decreased. Normo- and hyperglycaemic cells accumulated cholesteryl esters from modified LDL to a greater extent than control LDL, but total and individual cholesteryl ester accumulation was not affected by glucose levels. It is concluded that, whilst macrophage scavenger receptor mRNA and protein levels can be modulated by high glucose, these are not key factors in lipid accumulation by human macrophages under the conditions examined.

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Spiridonov, A. N., A. D. Khudiakova, and Yu I. Ragino. "Adipokines/cytokines and disturbances in lipid metabolism." Ateroscleroz 18, no. 2 (July 20, 2022): 157–64. http://dx.doi.org/10.52727/2078-256x-2022-18-2-157-164.

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This review presents the results of investigations in the field of studying the association of adipokines secreted by visceral adipocytes and the level of low-density lipoprotein cholesterol. In relation to this association, such adipokines as adiponectin, plasminogen activator inhibitor 1 (PAI-1), resistin, interleukin 1 beta (IL-1β), monocyte-chemoattractant protein type 1 (MCP-1), nerve growth factor (NGF), visfatin, omentin-1, and the pancreatic hormone insulin were analyzed. The results of studies that have studied the pathogenetic (in animal models) and clinical role of this association in humans are presented. Information on the topic from the publications of the PubMed, Google Scholar databases was used.

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Garofallo, Silvia Bueno, Vera Lucia Portal, Melissa Medeiros Markoski, Lucinara Dadda Dias, Alexandre Schaan de Quadrosa, and Aline Marcadenti. "Correlations between Traditional and Nontraditional Indicators of Adiposity, Inflammation, and Monocyte Subtypes in Patients with Stable Coronary Artery Disease." Journal of Obesity 2019 (July 3, 2019): 1–11. http://dx.doi.org/10.1155/2019/3139278.

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Background. Recruitment of monocytes and low-grade inflammation process are both involved in obesity and in atherosclerosis. Thus, the aim of this study was to evaluate the correlation among indicators of adiposity, monocyte subtypes, and inflammatory markers in patients with stable coronary artery disease (CAD). Methods. This was a cross-sectional study including 97 patients with stable CAD aged >40 years. Traditional anthropometric indicators of adiposity (body mass index (BMI); waist, hip, and neck circumferences; and waist-hip ratio) and nontraditional anthropometric indicators of adiposity (lipid accumulation product index (LAP), visceral adiposity index (VAI), and deep-abdominal-adipose-tissue index (DAAT)) were determined. Immunoprecipitation, turbidimetry, coagulometric method, and CBA were used for the evaluation of inflammatory markers (hs-CRP, IL-2, IL-4, IL-6, IL-10, and INF-γ). Monocyte subtypes were identified by flow cytometry and defined as CD14++ CD16− (Mon1), CD14++ CD16+ (Mon2), and CD14+ CD16++ (Mon3). Pearson’s correlation coefficient and adjusted partial correlation were calculated. Results. Monocyte subtypes were correlated with inflammation regardless of nutritional status according to BMI. In overweight individuals, LAP was correlated with IL-4 and fibrinogen (P<0.01 and P<0.05, respectively) and VAI with IL-4 (P<0.05). In obese patients, the BMI, waist, neck, and hip circumferences, and DAAT were correlated with IL-6 (P<0.05), regardless of age and sex. The hip circumference was correlated positively with Mon1 (r = 0.40, P=0.007) and negatively with Mon3 (r = −0.35, P=0.02) in obese subjects. Conclusion. Monocyte subtypes are correlated with inflammation in patients with stable CAD independently of BMI, whereas traditional and nontraditional indicators of adiposity are correlated differently with inflammatory markers and monocytes, according to the nutritional status.

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Elstad, M. R., S. M. Prescott, T. M. McIntyre, and G. A. Zimmerman. "Synthesis and release of platelet-activating factor by stimulated human mononuclear phagocytes." Journal of Immunology 140, no. 5 (March 1, 1988): 1618–24. http://dx.doi.org/10.4049/jimmunol.140.5.1618.

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Abstract Platelet-activating factor (PAF) is a potent phospholipid mediator that may participate in inflammatory responses by virtue of its ability to activate platelets, leukocytes, and vascular cells. We examined the synthesis and release of PAF by human peripheral blood monocytes (PBM) isolated by countercurrent elutriation. PAF was produced after stimulation by calcium ionophore A23187 (IoA), opsonized zymosan (OpsZ), and PMA with a relative order of potency IoA much greater than OpsZ greater than PMA. The portion of PAF subsequently released from the cell was dependent on the specific agonist, the time of incubation, and the presence of albumin. Under optimal conditions, PBM released 67, 49 and 32% of the total PAF produced in response to IoA, OpsZ, and PMA, respectively. Changes in PAF metabolism were observed in PBM that were examined after short term adherence or differentiation into macrophages. Adherent PBM accumulated and released less PAF than suspended monocytes, and monocyte-derived macrophages produced less PAF than the parent PBM. The ability of monocytes to release significant amounts of newly synthesized PAF from the cell is unusual among human cell types, which in general retain the vast majority of the lipid, and may be of particular pathophysiologic importance.

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Martinez, Shannalee R., Carla Barrientos Risso, Ralphdy Vergne, Nathan R. Wall, Julie Dutil, Carlos A. Casiano, Gilberto Ruiz-Deya, and Carlos Joel Diaz Osterman. "Abstract 2559: Tumor lipogenesis influences macrophage polarization in advanced prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2559. http://dx.doi.org/10.1158/1538-7445.am2022-2559.

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Abstract Aberrant lipid metabolism in prostate tumors is linked to aggressive disease and poor outcomes. The purpose of this study was to identify mechanisms by which lipid metabolism in prostate cancer cells influences the tumor immune microenvironment, with emphasis on the activation of macrophages. Our hypothesis that fatty acid synthase-driven de novo lipogenesis promotes immune evasion via alternative M2-like macrophage activation was tested using human monocyte (U937)-derived macrophages co-cultured with prostate cancer cells in the presence of fatty acid synthase inhibitors. Monocytes were differentiated to macrophages in vitro using phorbol-12-myristate-13-acetate for 48 hours prior to co-culture with prostate cancer cells. Macrophage polarization following co-culture with prostate cancer cells was evaluated using multi-parameter flow cytometry to detect established M1 (CD80, CD86) and M2 (CD163, CD206) markers. Furthermore, the expression of fatty acid synthase and pan-macrophage marker CD68 in human prostate tumor tissue microarrays was evaluated using multiplex immunohistochemistry. The lipogenic enzyme and macrophage staining correlated with disease progression, reaching peak levels in metastatic tissues. These findings indicate that tumoral fatty acid synthase is an important mediator of tumor-immune crosstalk, particularly in the context of aggressive and metastatic prostate cancer. These data further suggest that fatty acid synthesis represents a targetable complement to immune-enhancing therapies by modulating tumor cell metabolism, underscoring the need for further evaluation of agents targeting lipid metabolism in prostate cancer. Citation Format: Shannalee R. Martinez, Carla Barrientos Risso, Ralphdy Vergne, Nathan R. Wall, Julie Dutil, Carlos A. Casiano, Gilberto Ruiz-Deya, Carlos Joel Diaz Osterman. Tumor lipogenesis influences macrophage polarization in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2559.

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Szatmari, Istvan, Daniel Töröcsik, Maura Agostini, Tibor Nagy, Mark Gurnell, Endre Barta, Krishna Chatterjee, and Laszlo Nagy. "PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism." Blood 110, no. 9 (November 1, 2007): 3271–80. http://dx.doi.org/10.1182/blood-2007-06-096222.

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Abstract Activation of the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) modifies the immunophenotype of monocyte-derived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.

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Fraser, Merryn, Weidong Jing, Stefan Bröer, Florian Kurth, Leif-Erik Sander, Kai Matuschewski, and Alexander G. Maier. "Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells." PLOS Pathogens 17, no. 2 (February 18, 2021): e1009259. http://dx.doi.org/10.1371/journal.ppat.1009259.

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The human malaria parasite Plasmodium falciparum relies on lipids to survive; this makes its lipid metabolism an attractive drug target. The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of P. falciparum-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of Plasmodium falciparum-infected erythrocytes for in vivo interactions with the host immune system, and provide a rationale for targeted antimalarial drug design.

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Fernandez-Ruiz, Irene, Patrycja Puchalska, Chandrakala Aluganti Narasimhulu, Bhaswati Sengupta, and Sampath Parthasarathy. "Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading." Journal of Lipid Research 57, no. 4 (February 2, 2016): 574–86. http://dx.doi.org/10.1194/jlr.m062752.

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Roullet, J. B., M. Haluska, O. Morchoisne, and D. A. McCarron. "1,25-Dihydroxyvitamin D3-induced alterations of lipid metabolism in human monocyte-macrophages." American Journal of Physiology-Endocrinology and Metabolism 257, no. 2 (August 1, 1989): E290—E295. http://dx.doi.org/10.1152/ajpendo.1989.257.2.e290.

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An in vivo atherogenic role of dietary vitamin D has been postulated. To address this hypothesis we sought to determine the in vitro effects of its active circulating metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on lipid metabolism in human monocyte-derived macrophages. When cultured 6 days in the presence of 10(-8) M 1,25(OH)2D3 monocyte-macrophages accumulated significantly more triglycerides than control cells: 987.6 +/- 26.8 vs. 779.3 +/- 24.1 micrograms/mg protein (P less than 0.001). Triglyceride accumulation was associated with a hormone-induced stimulation of triglyceride synthesis as determined by [3H]oleate incorporation into cellular triglycerides. The effect of the hormone was significant after 24 h and dose dependent [10(-11) to 10(-8) M 1,25(OH)2D3]. It was specific since 10(-7) M 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 did not stimulate triglyceride synthesis, and its magnitude decreased from 1 to 9 days of culture. 1,25(OH)2D3 (10(-8) M) modified the cholesteryl ester metabolism of monocyte-macrophages only in the presence of acetylated low-density lipoproteins (50 micrograms/ml); it induced a significant increase of cellular cholesteryl ester content (21.9 +/- 1.1 vs. 11.7 +/- 1.7 micrograms/mg protein; P less than 0.001) and of esterification rate of cholesterol measured by [3H]oleate incorporation into cellular cholesteryl esters (17.2 +/- 0.9 vs. 6.5 +/- 0.3 nmol.mg protein-1.24 h-1; P less than 0.001) by comparison with control cells. These results show that 1,25(OH)2D3 alters in vitro lipid metabolism in the human monocyte-macrophage and suggest a new in vivo role for the hormone.

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Rull, Anna, Joan Carles Escolà-Gil, Josep Julve, Noemí Rotllan, Laura Calpe-Berdiel, Blai Coll, Gerard Aragonès, et al. "Deficiency in monocyte chemoattractant protein-1 modifies lipid and glucose metabolism." Experimental and Molecular Pathology 83, no. 3 (December 2007): 361–66. http://dx.doi.org/10.1016/j.yexmp.2007.08.003.

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Journal articles on the topic 'Monocytic lipid metabolism'

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