Journal articles on the topic 'Macrophage'
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1
Rodriguez, Eric, Frederic Boudard, Michele Mallié, Jean-Marie Bastide, and Madeleine Bastide. "Murine macrophage elastolytic activity induced by Aspergillus fumigatus strains in vitro: evidence of the expression of two macrophage-induced protease genes." Canadian Journal of Microbiology 43, no. 7 (July 1, 1997): 649–57. http://dx.doi.org/10.1139/m97-092.
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The interaction between Aspergillus fumigatus conidia and murine macrophages of various origins was investigated. Cocultures were carried out between A. fumigatus strains and freshly isolated murine pulmonary alveolar macrophages or two murine macrophage cell-lines: murine alveolar cell-line MALU and murine astrocytoma cell-line J774. By measuring the variation of elastolytic activity in the coculture supernatants with two elastin substrates, we demonstrated that either viable or fixed A. fumigatus or C. albicans yeasts or nonspecific particles induced significant macrophage elastolytic activity. The effect of A. fumigatus supernatant or the purified A. fumigatus galactomannan suggested also the possible involvement of this polysaccharide in macrophage-protease gene expression, release, and activity in invasive aspergillosis. The effect of inhibitory compounds demonstrated the potential implication of a macrophagic metalloprotease and a macrophagic cysteine protease. RNA analysis allowed us to demonstrate the induction of expression of two macrophagic protease genes in stimulated macrophages. Two distinctive mechanisms appeared to be implicated in macrophage protease induction: nonspecific phagocytosis in the earliest times of the coculture and (or) specific galactomannan recognition after its gradual release by the mycelium.Key words: Aspergillus fumigatus, macrophages, proteases, invasive aspergillosis, galactomannan.
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Liu, Shuangqing, Huilei Zhang, Yanan Li, Yana Zhang, Yangyang Bian, Yanqiong Zeng, Xiaohan Yao, et al. "S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation." Journal for ImmunoTherapy of Cancer 9, no. 6 (June 2021): e002548. http://dx.doi.org/10.1136/jitc-2021-002548.
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BackgroundThe peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization of tumor-associated macrophages (TAMs). However, upstream factors determining PPAR-γ upregulation in TAM protumor polarization are not fully identified. S100A4 plays crucial roles in promotion of cancer malignancy and mitochondrial metabolism. The fact that macrophage-derived S100A4 is major source of extracellular S100A4 suggests that macrophages contain a high abundance of intracellular S100A4. However, whether intracellular S100A4 in macrophages also contributes to cancer malignancy by enabling TAMs to acquire M2-like protumor activity remains unknown.MethodsGrowth of tumor cells was evaluated in murine tumor models. TAMs were isolated from the tumor grafts in whole-body S100A4-knockout (KO), macrophage-specific S100A4-KO and transgenic S100A4WT−EGFP mice (expressing enhanced green fluorescent protein (EGFP) under the control of the S100A4 promoter). In vitro induction of macrophage M2 polarization was conducted by interleukin 4 (IL-4) stimulation. RNA-sequencing, real-time quantitative PCR, flow cytometry, western blotting, immunofluorescence staining and mass spectrometry were used to determine macrophage phenotype. Exogenous and endogenous FAO, FA uptake and measurement of lipid content were used to analyze macrophage metabolism.ResultsTAMs contain two subsets based on whether they express S100A4 or not and that S100A4+ subsets display protumor phenotypes. S100A4 can be induced by IL-4, an M2 activator of macrophage polarization. Mechanistically, S100A4 controls the upregulation of PPAR-γ, a transcription factor required for FAO induction during TAM protumor polarization. In S100A4+ TAMs, PPAR-γ mainly upregulates CD36, a FA transporter, to enhance FA absorption as well as FAO. In contrast, S100A4-deficient TAMs exhibited decreased protumor activity because of failure in PPAR-γ upregulation-dependent FAO induction.ConclusionsWe find that macrophagic S100A4 enhances protumor macrophage polarization as a determinant of PPAR-γ-dependent FAO induction. Accordingly, our findings provide an insight into the general mechanisms of TAM polarization toward protumor phenotypes. Therefore, our results strongly suggest that targeting macrophagic S100A4 may be a potential strategy to prevent TAMs from re-differentiation toward a protumor phenotype.
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Wilson, Justin E., Bhuvana Katkere, and James R. Drake. "Francisella tularensis Induces Ubiquitin-Dependent Major Histocompatibility Complex Class II Degradation in Activated Macrophages." Infection and Immunity 77, no. 11 (August 24, 2009): 4953–65. http://dx.doi.org/10.1128/iai.00844-09.
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ABSTRACT The intracellular bacterium Francisella tularensis survives and replicates within macrophages, ultimately killing the host cell. Resolution of infection requires the development of adaptive immunity through presentation of F. tularensis antigens to CD4+ and CD8+ T cells. We have previously established that F. tularensis induces macrophage prostaglandin E2 (PGE2) production, leading to skewed T-cell responses. PGE2 can also downregulate macrophage major histocompatibility complex (MHC) class II expression, suggesting that F. tularensis-elicited PGE2 may further alter T-cell responses via inhibition of class II expression. To test this hypothesis, gamma interferon (IFN-γ)-activated reporter macrophages were exposed to supernatants from F. tularensis-infected macrophages, and the class II levels were measured. Exposure of macrophages to infection supernatants results in essentially complete clearance of surface class II and CD86, compromising the macrophage's ability to present antigens to CD4 T cells. Biochemical analysis revealed that infection supernatants elicit ubiquitin-dependent class II downregulation and degradation within intracellular acidic compartments. By comparison, exposure to PGE2 alone only leads to a minor decrease in macrophage class II expression, demonstrating that a factor distinct from PGE2 is eliciting the majority of class II degradation. However, production of this non-PGE2 factor is dependent on macrophage cyclooxygenase activity and is induced by PGE2. These results establish that F. tularensis induces the production of a PGE2-dependent factor that elicits MHC class II downregulation in IFN-γ-activated macrophages through ubiquitin-mediated delivery of class II to lysosomes, establishing another mechanism for the modulation of macrophage antigen presentation during F. tularensis infection.
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Pedicillo, Maria Carmela, Ilenia Sara De Stefano, Rosanna Zamparese, Raffaele Barile, Mario Meccariello, Alessio Agostinone, Giuliana Villani, et al. "The Role of Toll-like Receptor-4 in Macrophage Imbalance in Lethal COVID-19 Lung Disease, and Its Correlation with Galectin-3." International Journal of Molecular Sciences 24, no. 17 (August 26, 2023): 13259. http://dx.doi.org/10.3390/ijms241713259.
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To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage’s sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1(+) and Spike-1(−) lungs (p < 0.0001), and a macrophage shift with important down-regulation of GAL-3(+) alveolar macrophages associated with Spike-1 persistence (p < 0.05), in favor of CD163(+) myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19.
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Fahey, T. J., K. J. Tracey, P. Tekamp-Olson, L. S. Cousens, W. G. Jones, G. T. Shires, A. Cerami, and B. Sherry. "Macrophage inflammatory protein 1 modulates macrophage function." Journal of Immunology 148, no. 9 (May 1, 1992): 2764–69. http://dx.doi.org/10.4049/jimmunol.148.9.2764.
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Abstract Macrophage inflammatory protein 1 (MIP 1), initially purified from the conditioned medium of endotoxin-stimulated macrophages, is a low m.w. heparin-binding protein doublet comprising two peptides, MIP 1 alpha and MIP 1 beta. Although native doublet MIP 1 has previously been shown to exert pyrogenic, mitogenic, and proinflammatory effects on other cell types, its actions on its cell of origin, the macrophage, have not been well catalogued. Our study reports several aspects of macrophage function that are modulated by MIP 1. MIP 1 was not directly cytotoxic for WEHI tumor cells, but MIP 1-treated macrophage exhibited enhanced antibody-independent macrophage cytotoxicity for tumor targets. MIP 1 treatment stimulated proliferation of mature tissue macrophages, and this effect was enhanced upon costimulations with either CSF-1 or granulocyte-macrophage-CSF. Thioglycollate-elicited peritoneal exudate macrophages incubated with native doublet MIP 1-secreted bioactive TNF and IL-6, as well as immunoreactive IL-1 alpha, and these effects were enhanced significantly when the cells were costimulated with IFN-gamma. Purified preparations of the recombinantly derived MIP 1 alpha peptide alone stimulated the secretion of TNF, IL-1 alpha, and IL-6 by peritoneal macrophages, but MIP 1 beta did not. In fact, as little as eightfold excess MIP 1 beta blocked TNF-induction by MIP 1 alpha to a significant degree. By contrast to these apparent "macrophage activating" properties of MIP 1, the cytokine failed to trigger the macrophage oxidative burst, or to up-regulate the expression of Ia on the macrophage surface. Taken together, these data reveal that MIP 1 peptides act as autocrine modulators of their cells of origin, and raise the possibility that MIP 1 peptides may play a role in modulating macrophage responses to inflammatory stimuli in vivo.
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Xu, Jiawei, Lanya Fu, Junyao Deng, Jiaqi Zhang, Ying Zou, Liqiang Liao, Xinrui Ma, et al. "miR-301a Deficiency Attenuates the Macrophage Migration and Phagocytosis through YY1/CXCR4 Pathway." Cells 11, no. 24 (December 7, 2022): 3952. http://dx.doi.org/10.3390/cells11243952.
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(1) Background: the miR-301a is well known involving the proliferation and migration of tumor cells. However, the role of miR-301a in the migration and phagocytosis of macrophages is still unclear. (2) Methods: sciatic nerve injury, liver injury models, as well as primary macrophage cultures were prepared from the miR-301a knockout (KO) and wild type (WT) mice to assess the macrophage’s migration and phagocytosis capabilities. Targetscan database analysis, Western blotting, siRNA transfection, and CXCR4 inhibition or activation were performed to reveal miR301a’s potential mechanism. (3) Results: the macrophage’s migration and phagocytosis were significantly attenuated by the miR-301a KO both in vivo and in vitro. MiR-301a can target Yin-Yang 1 (YY1), and miR-301a KO resulted in YY1 up-regulation and CXCR4 (YY1′s down-stream molecule) down-regulation. siYY1 increased the expression of CXCR4 and enhanced migration and phagocytosis in KO macrophages. Meanwhile, a CXCR4 inhibitor or agonist could attenuate or accelerate, respectively, the macrophage migration and phagocytosis. (4) Conclusions: current findings indicated that miR-301a plays important roles in a macrophage’s capabilities of migration and phagocytosis through the YY1/CXCR4 pathway. Hence, miR-301a might be a promising therapeutic candidate for inflammatory diseases by adjusting macrophage bio-functions.
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Careau, Éric, Léa-Isabelle Proulx, Philippe Pouliot, Annie Spahr, Véronique Turmel, and Élyse Y. Bissonnette. "Antigen sensitization modulates alveolar macrophage functions in an asthma model." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 5 (May 2006): L871—L879. http://dx.doi.org/10.1152/ajplung.00219.2005.
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We have previously demonstrated that adoptive transfer of alveolar macrophages from allergy-resistant rats to alveolar macrophage-depleted allergic rats prevents airway hyperresponsiveness development, suggesting an important role for alveolar macrophages in asthma pathogenesis. Given that ovalbumin sensitization can modulate alveolar macrophage cytokine production, we investigated the role of sensitized and unsensitized alveolar macrophages in an asthma model. Alveolar macrophages from unsensitized or sensitized Brown Norway rats were transferred to alveolar macrophage-depleted sensitized rats 24 h before allergen challenge. Airway responsiveness to methacholine and airway inflammation were measured the following day. Methacholine concentration needed to increase lung resistance by 200% was significantly higher in alveolar macrophage-depleted sensitized rats that received unsensitized alveolar macrophages compared with alveolar macrophage-depleted sensitized rats that received sensitized alveolar macrophages. Tumor necrosis factor levels in bronchoalveolar lavage fluid of sensitized rats that received unsensitized alveolar macrophages were significantly lower compared with rats that received sensitized alveolar macrophages. Interestingly, alveolar macrophages of unsensitized animals showed higher phagocytosis activity compared with alveolar macrophages of sensitized rats, suggesting that sensitization modulates alveolar macrophage phagocytosis function. Our data suggest an important role of allergen sensitization on alveolar macrophage function in asthma pathogenesis.
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McKenzie, C. G. J., U. Koser, L. E. Lewis, J. M. Bain, H. M. Mora-Montes, R. N. Barker, N. A. R. Gow, and L. P. Erwig. "Contribution of Candida albicans Cell Wall Components to Recognition by and Escape from Murine Macrophages." Infection and Immunity 78, no. 4 (February 1, 2010): 1650–58. http://dx.doi.org/10.1128/iai.00001-10.
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ABSTRACT The pathogenicity of the opportunistic human fungal pathogen Candida albicans depends on its ability to escape destruction by the host immune system. Using mutant strains that are defective in cell surface glycosylation, cell wall protein synthesis, and yeast-hypha morphogenesis, we have investigated three important aspects of C. albicans innate immune interactions: phagocytosis by primary macrophages and macrophage cell lines, hyphal formation within macrophage phagosomes, and the ability to escape from and kill macrophages. We show that cell wall glycosylation is critically important for the recognition and ingestion of C. albicans by macrophages. Phagocytosis was significantly reduced for mutants deficient in phosphomannan biosynthesis (mmn4Δ, pmr1Δ, and mnt3 mnt5Δ), whereas O- and N-linked mannan defects (mnt1Δ mnt2Δ and mns1Δ) were associated with increased ingestion, compared to the parent wild-type strains and genetically complemented controls. In contrast, macrophage uptake of mutants deficient in cell wall proteins such as adhesins (ece1Δ, hwp1Δ, and als3Δ) and yeast-locked mutants (clb2Δ, hgc1Δ, cph1Δ, efg1Δ, and efg1Δ cph1Δ), was similar to that observed for wild-type C. albicans. Killing of macrophages was abrogated in hypha-deficient strains, significantly reduced in all glycosylation mutants, and comparable to wild type in cell wall protein mutants. The diminished ability of glycosylation mutants to kill macrophages was not a consequence of impaired hyphal formation within macrophage phagosomes. Therefore, cell wall composition and the ability to undergo yeast-hypha morphogenesis are critical determinants of the macrophage's ability to ingest and process C. albicans.
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Torre, Donato, Luisa Gennero, F. M. Baccino, Filippo Speranza, Gilberto Biondi, and Agostino Pugliese. "Impaired Macrophage Phagocytosis of Apoptotic Neutrophils in Patients with Human Immunodeficiency Virus Type 1 Infection." Clinical and Vaccine Immunology 9, no. 5 (September 2002): 983–86. http://dx.doi.org/10.1128/cdli.9.5.983-986.2002.
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ABSTRACT Dysfunction of neutrophils (polymorphonuclear leukocytes [PMNL]) and macrophagic cells occurs as a consequence of human immunodeficiency virus type 1 (HIV-1) infection. Macrophages contribute to the resolution of early inflammation ingesting PMNL apoptotic bodies. This study investigated macrophage ability to phagocytose PMNL apoptotic bodies in patients with HIV-1 infection in comparison with uninfected individuals and the effect of HIV Nef protein on apoptotic body phagocytosis to determine if phagocytic activity is impaired by HIV infection. Monocytes/macrophages were isolated from 10 HIV-1-infected patients and from five healthy volunteers, whereas PMNL were isolated from healthy volunteers. Macrophage phagocytosis of apoptotic PMNL was determined by staining of apoptotic bodies with fluorescein-conjugated concanavalin A or with fluorescein-labeled phalloidin. Our data show significant impairment of PMNL apoptotic body macrophage phagocytosis in subjects with HIV-1 infection presenting a concentration of CD4+ T lymphocytes of >200/mm3 and in particular in those with <200 CD4+ T lymphocyte cells/mm3. In addition, HIV-1 recombinant Nef protein is able to decrease phagocytosis of apoptotic PMNL from normal human macrophages in a dose-dependent manner. The results of our study suggest that impaired macrophage phagocytosis of PMNL apoptotic bodies may contribute to the persistence of the inflammatory state in HIV-infected subjects, especially during opportunistic infections that are often favored by defective phagocytic activity.
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Dende, Chaitanya, Mihir Pendse, Daniel Propheter, Gabriella Quinn, and Lora V. Hooper. "Vitamin A regulates phagocytosis by resident macrophages of the small intestine." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 113.23. http://dx.doi.org/10.4049/jimmunol.208.supp.113.23.
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Abstract Intestinal Tim4+ CD4+ macrophages are a distinctive macrophage subset that express Tim4, a receptor for phosphatidylserine on dying apoptotic cells, Unlike other macrophage subsets, they do not depend on blood monocytes for their turnover, instead self-maintained in the small intestine. The signal(s) responsible for the self-maintenance and function of Tim4+ CD4+ macrophages is not known. We have discovered that maintenance of the gut resident Tim4+ CD4+ macrophage population depends on dietary vitamin A and its derivative retinoic acid (RA). Retinoic acid receptors, which direct RA-dependent transcription, were required for maintenance of Tim4+ CD4+ macrophages. Chemical blockade of retinoic acid receptor (RAR) signaling and macrophage-specific genetic inactivation of RARs in mice further revealed that macrophage-intrinsic RARα signaling was required for Timd4 expression and maintenance of Tim4+ CD4+ macrophages. Macrophage RARα signaling was furthermore essential for phagocytosis by Tim4+ CD4+ macrophages. Ongoing studies are examining the role of Tim4+ CD4+ macrophages and vitamin A in the clearance of apoptotic intestinal epithelial cells. Our findings reveal that vitamin A provides an essential dietary signal for the maintenance and function of a gut resident macrophage subset. Supported by Welch foundation grant I-1874
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Vuarchey, Clément, Sushil Kumar, and Reto Schwendener. "Albumin coated liposomes: a novel platform for macrophage specific drug delivery." Nanotechnology Development 1, no. 1 (July 19, 2011): 2. http://dx.doi.org/10.4081/nd.2011.e2.
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Here we report a new and efficient approach of macrophage specific drug delivery by coating liposomes with albumin. Activated albumin was reacted with liposomes containing polyethylene glycol (PEG) as hydrophilic spacers to create a flexible layer of covalently bound albumin molecules on the liposome surface. Albumin coated liposomes were taken up faster and more efficiently than uncoated liposomes by murine macrophages. Liposome uptake was significantly higher in macropha - ges as compared to other cell types tested (endothelial cells, fibroblasts, tumor cells), suggesting specificity for macrophages. In vivo, splenic macrophages phagocytosed BSA coated liposomes (BSA-L) at faster rates compared to conventional liposomes (L) and PEG liposomes (PEG-L). To prove the effectiveness of this new macrophage specific drug carrier, the bisphosphonates clodronate and zoledronate were encapsulated in BSA-L and compared with conventional liposomes. <em>In vitro</em>, treatment of macrophages with clodronate or zoledronate in BSA-L led to cytotoxic activity within a very short time and to up to 50-fold reduced IC50 concentrations. <em>In vivo</em>, clodronate encapsulated in BSA-L depleted splenic macrophages at a 5-fold lower concentration as conventional clodronate-liposomes. Our results highlight the pharmaceutical benefits of albumin-coated liposomes for macrophage specific drug delivery.
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Doherty, T. M., R. Kastelein, S. Menon, S. Andrade, and R. L. Coffman. "Modulation of murine macrophage function by IL-13." Journal of Immunology 151, no. 12 (December 15, 1993): 7151–60. http://dx.doi.org/10.4049/jimmunol.151.12.7151.
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Abstract Activated macrophages are important effector cells for immune response to many parasites and immune responses are strongly modulated in part by the effect of Th cell-derived cytokines on macrophages. Th1-derived cytokines such as IFN-gamma are strong stimulators of macrophage activation, while cytokines produced by Th2 cells, including IL-4 and IL-10, have been shown under some conditions to inhibit macrophage activities associated with inflammatory responses. IL-13, a recently described cytokine produced by Th2 cells, is also capable of down-modulating macrophage activity in a manner similar to that previously described for IL-4. Treatment of activated macrophages with IL-13 reduces the production of inflammatory monokines in response to IFN-gamma or LPS, both potent stimulators of these factors. In addition, IL-13 decreases the production of nitric oxide by activated macrophages. Nitric oxide has been implicated in both macrophage cytotoxicity and macrophage-associated immunosuppression. The suppression of nitric oxide by IL-13 leads to a decrease in parasiticidal activity by activated macrophages. However, our data indicate that IL-13 has pleiotropic effects, while the inflammatory potential of activated macrophages is significantly reduced, the potential of other macrophage subsets is unimpaired. These data indicate that IL-13 could be a potent modulator of immune responses in vivo, with effects that may embrace both macrophage suppressive and macrophage potentiating functions.
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Cotechini, Tiziana, Aline Atallah, and Arielle Grossman. "Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy." Cells 10, no. 4 (April 20, 2021): 960. http://dx.doi.org/10.3390/cells10040960.
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Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden.
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Taylor, Sarah A., Shang-Yang Chen, Gaurav Gadhvi, Liang Feng, Kyle D. Gromer, Hiam Abdala-Valencia, Kiwon Nam, et al. "Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations." PLOS ONE 16, no. 1 (January 7, 2021): e0244743. http://dx.doi.org/10.1371/journal.pone.0244743.
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Background & aims Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. Methods We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. Results We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. Conclusions We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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Aziz, Athar, Laurent Vanhille, Peer Mohideen, Louise M. Kelly, Claas Otto, Youssef Bakri, Noushine Mossadegh, Sandrine Sarrazin, and Michael H. Sieweke. "Development of Macrophages with Altered Actin Organization in the Absence of MafB." Molecular and Cellular Biology 26, no. 18 (September 15, 2006): 6808–18. http://dx.doi.org/10.1128/mcb.00245-06.
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ABSTRACT In the hematopoietic system the bZip transcription factor MafB is selectively expressed at high levels in monocytes and macrophages and promotes macrophage differentiation in myeloid progenitors, whereas a dominant-negative allele can inhibit this process. To analyze the requirement of MafB for macrophage development, we generated MafB-deficient mice and, due to their neonatal lethal phenotype, analyzed macrophage differentiation in vitro, in the embryo, and in reconstituted mice. Surprisingly we observed in vitro differentiation of macrophages from E14.5 fetal liver (FL) cells and E18.5 splenocytes. Furthermore we found normal numbers of F4/80+/Mac-1+ macrophages and monocytes in fetal liver, spleen, and blood as well as in bone marrow, spleen, and peritoneum of adult MafB−/− FL reconstituted mice. MafB−/− macrophages showed intact basic macrophage functions such as phagocytosis of latex beads or Listeria monocytogenes and nitric oxide production in response to lipopolysaccharide. By contrast, MafB−/− macrophages expressed increased levels of multiple genes involved in actin organization. Consistent with this, phalloidin staining revealed an altered morphology involving increased numbers of branched protrusions of MafB−/− macrophages in response to macrophage colony-stimulating factor. Together these data point to an unexpected redundancy of MafB function in macrophage differentiation and a previously unknown role in actin-dependent macrophage morphology.
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Song, Lili, Do-sung Kim, Wenyu Gou, Jingjing Wang, Ping Wang, Zhiguo Wei, Bei Liu, Zihai Li, Kemian Gou, and Hongjun Wang. "GRP94 regulates M1 macrophage polarization and insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 318, no. 6 (June 1, 2020): E1004—E1013. http://dx.doi.org/10.1152/ajpendo.00542.2019.
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Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.
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Pagan, Antonio, Chao-Tsung Yang, Laura Swaim, and Lalita Ramakrishnan. "Replenishment of granuloma macrophages promotes mycobacterial resistance by preventing extracellular bacterial growth (INC7P.410)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 186.11. http://dx.doi.org/10.4049/jimmunol.192.supp.186.11.
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Abstract Pathogenic mycobacteria exploit the early tuberculous granuloma for their expansion by inducing infected macrophage apoptosis and accelerating uninfected macrophage recruitment and infection upon engulfing the dying macrophages. Whether sustained macrophage recruitment to established granulomas is also host-detrimental is unclear. We addressed this question in the zebrafish model of tuberculosis by manipulating the macrophage colony stimulation factor 1 (CSF-1) pathway, which promotes macrophage development. Early granuloma formation was normal in CSF-1 receptor-deficient fish in spite of having fewer macrophages. However, they became hypersusceptible upon depleting their macrophages, leading to the sudden loss of new recruits that would normally engulf the infected dead cells. The unphagocytosed infected macrophages underwent necrosis, releasing mycobacteria into the extracellular milieu that promotes exuberant growth. Partial macrophage depletion with lipo-clodranate produced the same effects in wild-type fish. Conversely, overexpression of CSF-1 in wild-type fish increased macrophage numbers and reduced susceptibility to infection. These results suggest that granuloma kinetics must be nuanced to promote resistance - while delaying granuloma formation is host-beneficial, abolishing macrophage recruitment to established granulomas is detrimental. These results might also explain why monocytopenias confer susceptibility to mycobacterial infections in humans.
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Cho, Sun Wook, Young A. Kim, Hyun Jin Sun, Ye An Kim, Byung-Chul Oh, Ka Hee Yi, Do Joon Park, and Young Joo Park. "CXCL16 signaling mediated macrophage effects on tumor invasion of papillary thyroid carcinoma." Endocrine-Related Cancer 23, no. 2 (November 11, 2015): 113–24. http://dx.doi.org/10.1530/erc-15-0196.
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Macrophages in tumor microenvironment have pivotal roles in tumor growth, metastasis, and angiogenesis. We investigated the interacting mechanism of macrophage actions in human papillary thyroid cancer (PTC). Co-cultures of macrophage/PTC significantly increased the cancer cell migration potentials, compared with the PTC culture alone. Treatment of conditioned medium (CM) of macrophage/PTC co-cultures enhanced cell invasions in 3D invasion assay. Cytokine array analysis demonstrated that CM of macrophage/PTC co-cultures contained a high level of CXCL16, while it was not found in CM of PTC culture alone. Treatment with CXCL16 enhanced the cell migration potentials in PTC cells, and blocking CXCL16 signaling using anti-CXCL16 antibody or metalloproteinase inhibitor (TAPI2) attenuated macrophage-mediated enhancement of PTC cell migration potentials. In PTC cells, CXCL16 treatment or co-cultures with macrophages increased Akt phosphorylation, and these macrophage-dependent increases of Akt phosphorylation was inhibited by anti-CXCL16 antibody. Moreover, Akt inhibitor attenuated macrophage-mediated increases of PTC cell migration potential. In macrophages, treatment of macrophage/PTC co-cultured CMs up-regulated CD163, Il10, and CD206, which were attenuated by anti-CXCL16 antibody treatment. Finally, CXCR6 and CXCL16 expressions were evaluated by immunohistochemical staining with a thyroid tissue microarray including 136 PTC. CXCR6 expressions showed positive correlation with the density of CD163+ macrophages and associated with lymph node metastasis. In conclusion, CXCL16 signaling partly mediated macrophage actions on PTC tumor cell invasion and also changed the macrophage phenotypes into M2-macrophages in PTC tumor microenvironment. These data suggested that CXCL16 signaling, a bidirectional player in macrophage-associated tumor microenvironment, might be a potential therapeutic target of human PTC.
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Tekin, Cansu, Hella L. Aberson, Cynthia Waasdorp, Gerrit K. J. Hooijer, Onno J. de Boer, Frederike Dijk, Maarten F. Bijlsma, and C. Arnold Spek. "Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation." Cellular Oncology 43, no. 6 (August 18, 2020): 1161–74. http://dx.doi.org/10.1007/s13402-020-00549-x.
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Abstract Purpose Targeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored. Here we address the PAR1-macrophage-tumor cell crosstalk and assess its contributions to tumor progression. Methods PAR1 expression and macrophage infiltration were correlated in primary PDAC biopsies using gene expression datasets and tissue microarrays. Medium transfer experiments were used to evaluate the functional consequences of macrophage-tumor cell crosstalk and to assess the contribution of PAR1 to the observed responses. PAR1 cleavage assays were used to identify a macrophage-secreted PAR1 agonist, and the effects of candidate proteases were assessed in medium transfer experiments with specific inhibitors and/or recombinant agonist. Results PAR1 expression correlates with macrophage infiltration in primary PDACs, and macrophages induce mesenchymal transition of PDAC cells through PAR1 activation. Protease profiling identified macrophage-secreted matrix metalloprotease 9 (MMP9) as the relevant PAR1 agonist in PDAC. PAR1 and/or MMP9 inhibition limited macrophage-driven mesenchymal transition. Likewise, preventing mesenchymal transition by silencing ZEB1 or by pharmacological inhibition of the MMP9/PAR1 axis significantly reduced the ability of tumor cells to survive the anti-tumor activities of macrophages. Conclusion Macrophages secrete MMP9, which acts upon PDAC cell PAR1 to induce mesenchymal transition. This macrophage-induced mesenchymal transition supports the tumor-promoting role of macrophage influx, explaining the dichotomous contributions of these immune cells to tumor growth.
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Lu, Chunxia, P. Anil Kumar, Yong Fan, Mark A. Sperling, and Ram K. Menon. "A Novel Effect of Growth Hormone on Macrophage Modulates Macrophage-Dependent Adipocyte Differentiation." Endocrinology 151, no. 5 (February 25, 2010): 2189–99. http://dx.doi.org/10.1210/en.2009-1194.
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The GH receptor (GHR) is expressed on macrophages. However, the precise role of GH in regulation of macrophage function is unclear. We hypothesized that soluble factors including cytokines produced by macrophages in a GH-dependent manner regulate adipogenesis. We confirmed expression and functional integrity of the GHR in the J774A.1 macrophage cells. Conditioned medium (CM) from macrophages inhibited adipogenesis in a 3T3-L1 adipogenesis assay. CM from GH-treated macrophages decreased the inhibitory effect of CM from macrophages on adipogenesis. This effect on preadipocyte differentiation was active only during the first (early) phase of adipocyte differentiation. CM from stromal vascular compartment macrophages of mice with macrophage-specific deletion of the GHR exhibited more inhibitory effect on 3T3-L1 preadipocyte differentiation compared with CM from stromal vascular compartment macrophages of control mice, indicating that intact GH action in primary macrophages also increases preadipocyte differentiation. GH did not increase IGF-1 expression in macrophages. PCR array analysis identified IL-1β as a candidate cytokine whose expression was altered by GH in macrophages. Levels of IL-1β mRNA and protein were significantly decreased in GH-treated J774A.1 macrophages. Nuclear factor-κB stimulates IL-1β gene expression, and GH induced a significant decrease in the levels of phosphorylated nuclear factor-κB in macrophages. IL-1β is a known inhibitor of adipogenesis, and these results support GH-dependent down-regulation of macrophage IL-1β expression as one mechanism for the observed increase in adipogenesis with CM from GH-treated macrophages. We conclude that GH decreases secretion of IL-1β by the macrophage and thus in a paracrine manner increases adipocyte differentiation. These results provide a novel mechanism for GH’s actions in the control of adipogenesis.
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Lee, Hanui, Seong Hee Kang, Gyeong Han Jeong, Seoung Sik Lee, Byung Yeoup Chung, Geun-Joong Kim, and Hyoung-Woo Bai. "Gamma irradiation-engineered macrophage-derived exosomes as potential immunomodulatory therapeutic agents." PLOS ONE 19, no. 6 (June 12, 2024): e0303434. http://dx.doi.org/10.1371/journal.pone.0303434.
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The modulation of macrophage polarization is a promising strategy for maintaining homeostasis and improving innate and adaptive immunity. Low-dose ionizing radiation has been implicated in macrophage immunomodulatory responses. However, studies on the relationship between exosomes and regulation of macrophage polarization induced by ionizing radiation are limited. Therefore, this study investigated the alterations in macrophages and exosomes induced by gamma irradiation and elucidated the underlying mechanisms. We used the mouse macrophage cell line RAW 264.7 to generate macrophages and performed western blot, quantitative reverse transcription-PCR, and gene ontology analyses to elucidate the molecular profiles of macrophage-derived exosomes under varying treatment conditions, including 10 Gy gamma irradiation. Exosomes isolated from gamma-irradiated M1 macrophages exhibited an enhanced M1 phenotype. Irradiation induced the activation of NF-κB and NLRP3 signaling in M1 macrophages, thereby promoting the expression of pro-inflammatory cytokines. Cytokine expression was also upregulated in gamma-irradiated M1 macrophage-released exosomes. Therefore, gamma irradiation has a remarkable effect on the immunomodulatory mechanisms and cytokine profiles of gamma-irradiated M1 macrophage-derived exosomes, and represents a potential immunotherapeutic modality.
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Deng, Lishuang, Zhijie Jian, Tong Xu, Fengqin Li, Huidan Deng, Yuancheng Zhou, Siyuan Lai, Zhiwen Xu, and Ling Zhu. "Macrophage Polarization: An Important Candidate Regulator for Lung Diseases." Molecules 28, no. 5 (March 4, 2023): 2379. http://dx.doi.org/10.3390/molecules28052379.
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Macrophages are crucial components of the immune system and play a critical role in the initial defense against pathogens. They are highly heterogeneous and plastic and can be polarized into classically activated macrophages (M1) or selectively activated macrophages (M2) in response to local microenvironments. Macrophage polarization involves the regulation of multiple signaling pathways and transcription factors. Here, we focused on the origin of macrophages, the phenotype and polarization of macrophages, as well as the signaling pathways associated with macrophage polarization. We also highlighted the role of macrophage polarization in lung diseases. We intend to enhance the understanding of the functions and immunomodulatory features of macrophages. Based on our review, we believe that targeting macrophage phenotypes is a viable and promising strategy for treating lung diseases.
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Shaw, Maureen A., Zhen Gao, and Eric S. Mullins. "Plasmin(ogen) Mediates Macrophage Migration in a Fibrin(ogen) Dependent Mechanism." Blood 128, no. 22 (December 2, 2016): 18. http://dx.doi.org/10.1182/blood.v128.22.18.18.
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Abstract Mounting evidence ties both fibrin(ogen) and plasmin(ogen) to inflammatory diseases. Indeed, both fibrin(ogen) and plasmin(ogen) have been linked to critical macrophage functions in multiple disease processes. Migration of macrophages to sites of sterile inflammation is, at least partially, dependent on plasmin(ogen). Mice lacking plasminogen, when challenged with sterile thioglycollate-induced peritonitis, have both diminished overall leukocyte migration and decreased macrophage migration. Additionally, macrophage migration defects have been identified in both mice lacking plasminogen and plasminogen receptors. Plasmin has many targets that may play a role in supporting macrophage migration. In addition to proteolysis of fibrin(ogen), plasmin activates matrix metalloprotease (MMP) 2 and MMP9 and cleaves collagen and laminin. Indeed, mice that lack MMP9 have a migration defect similar to mice that lack plasminogen, suggesting that MMP9 is a biologically relevant proteolytic target in this context. To further examine the targets of plasmin that regulate macrophage migration, we challenged animals that have individual and combined genetic deficiencies in fibrinogen and plasminogen with thioglycollate-induced peritonitis. We have found that mice that lack fibrinogen alone have a significantly increased migration of macrophages to the peritoneal cavity. Mice with lack of plasminogen alone demonstrated the expected diminution in macrophage migration to the peritoneal cavity. However, mice that were deficient in both plasminogen and fibrinogen demonstrated macrophage migration that was indistinguishable from wildtype. These data suggest that fibrin(ogen) impedes macrophage migration to the peritoneal cavity. To further confirm this mechanism, we examined macrophage migration in a transwell assay in vitro, in response to macrophage chemoattractant protein-1 (MCP-1). Here, a macrophage cell line (RAW 264.7) migration was examined in the absence and presence of fibrin matrices. Macrophages, in the absence of plasminogen, did demonstrate a modest, but statistically significant, increase in migration across the transwell membrane in the absence of fibrinogen. When a fibrin matrix was generated on the transwell membrane, macrophages were essentially unable to cross in the absence of plasminogen. These data further support the concept that macrophages require plasmin(ogen) to cross fibrin matrices. To further explore the plasmin(ogen)-fibrin(ogen) interaction in macrophage migration, we assessed the migration of macrophages to fibrin degradation products (FDPs). First, we examined macrophage transwell migration in response to MCP-1 in the presence of FDPs to assess if FDPs impede macrophage migration. Instead of impeding macrophage migration, FDPs significantly increased macrophage migration across the transwell membrane. Indeed FDPs initiated macrophage migration even in the absence of MCP-1. To confirm that this was FDP induced migration, and not direct plasmin signaling on macrophages, we examined macrophage migration to FDPs in the presence of an irreversible plasmin inhibitor. We again found that plasmin degradation of fibrin was needed for migration, however, further plasmin activity was not required. Taken together, these data suggest that macrophages require plasmin(ogen) to navigate fibrin matrices and that the by-product of this degradation (FDPs) is a signal for additional macrophage migration to sites of fibrin deposition. Disclosures Mullins: Baxalta (now part of Shire): Honoraria; US WorldMeds: Membership on an entity's Board of Directors or advisory committees.
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Xie, Linglin, M. Teresa Ortega, Silvia Mora, and Stephen K. Chapes. "Interactive Changes between Macrophages and Adipocytes." Clinical and Vaccine Immunology 17, no. 4 (February 17, 2010): 651–59. http://dx.doi.org/10.1128/cvi.00494-09.
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ABSTRACT Obesity is associated with a proinflammatory state, with macrophage infiltration into adipose tissue. We tested the hypothesis that communication between macrophages and adipocytes affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function. To test this hypothesis, we cocultured 3T3-L1 adipocytes with C2D macrophages or primary peritoneal mouse macrophages and examined the impacts of macrophages and adipocytes on each other. Adipocytes and preadipocytes did not affect C2D macrophage TNF- α, IL-6, or IL-1 β transcript concentrations relative to those obtained when C2D macrophages were incubated alone. However, preadipocytes and adipocytes increased PEC-C2D macrophage IL-6 transcript levels, while preadipocytes inhibited IL-1 β transcript levels compared to those obtained when PEC-C2D macrophages were incubated in medium alone. We found that adipocyte coculture increased macrophage consumption of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and, in some cases, IL-6. C2D macrophages increasingly downregulated GLUT4 transcript levels in differentiated adipocytes. Recombinant TNF-α, IL-1β, and IL-6 also downregulated GLUT4 transcript levels relative to those for the control. However, only IL-6 was inhibitory at concentrations detected in macrophage-adipocyte cocultures. IL-6 and TNF-α, but not IL-1β, inhibited Akt phosphorylation within 15 min of insulin stimulation, but only IL-6 was inhibitory 30 min after stimulation. Lastly, we found that adipocyte differentiation was inhibited by macrophages or by recombinant TNF-α, IL-6, and IL-1β, with IL-6 having the most impact. These data suggest that the interaction between macrophages and adipocytes is a complex process, and they support the hypothesis that the macrophage-adipocyte interaction affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function.
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Chen, BD, CR Clark, and TH Chou. "Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor." Blood 71, no. 4 (April 1, 1988): 997–1002. http://dx.doi.org/10.1182/blood.v71.4.997.997.
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Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a specific humoral growth factor that stimulates both neutrophilic granulocyte and macrophage production by bone marrow hematopoietic progenitor cells. GM-CSF also stimulates the proliferation and clonal growth of both tissue macrophages and blood monocytes. Although at low concentrations GM-CSF was unable to support the long-term growth of tissue macrophages, it greatly enhanced their responsiveness to macrophage CSF (M-CSF, or CSF-1). This effect was also observed by treating macrophages with GM-CSF for a short time. GM-CSF did not compete with M-CSF for binding to M-CSF receptors nor was it inactivated by treatment with anti-M-CSF antiserum. Treatment of tissue macrophages with GM-CSF led to a rapid but transient downregulation of M-CSF receptors; prolonged incubation at 37 degrees C, however, resulted in a restoration and upregulation of M-CSF receptors. Identical effects were observed with both native or recombinant GM-CSF. This study suggests that GM-CSF regulates tissue macrophage production by two modes of action: (a) direct stimulation of macrophage proliferation, and (b) enhancement of their responsiveness to M-CSF.
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Chen, BD, CR Clark, and TH Chou. "Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor." Blood 71, no. 4 (April 1, 1988): 997–1002. http://dx.doi.org/10.1182/blood.v71.4.997.bloodjournal714997.
Full textAbstract:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a specific humoral growth factor that stimulates both neutrophilic granulocyte and macrophage production by bone marrow hematopoietic progenitor cells. GM-CSF also stimulates the proliferation and clonal growth of both tissue macrophages and blood monocytes. Although at low concentrations GM-CSF was unable to support the long-term growth of tissue macrophages, it greatly enhanced their responsiveness to macrophage CSF (M-CSF, or CSF-1). This effect was also observed by treating macrophages with GM-CSF for a short time. GM-CSF did not compete with M-CSF for binding to M-CSF receptors nor was it inactivated by treatment with anti-M-CSF antiserum. Treatment of tissue macrophages with GM-CSF led to a rapid but transient downregulation of M-CSF receptors; prolonged incubation at 37 degrees C, however, resulted in a restoration and upregulation of M-CSF receptors. Identical effects were observed with both native or recombinant GM-CSF. This study suggests that GM-CSF regulates tissue macrophage production by two modes of action: (a) direct stimulation of macrophage proliferation, and (b) enhancement of their responsiveness to M-CSF.
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Mouton, Alan J., Xuan Li, Michael E. Hall, and John E. Hall. "Obesity, Hypertension, and Cardiac Dysfunction." Circulation Research 126, no. 6 (March 13, 2020): 789–806. http://dx.doi.org/10.1161/circresaha.119.312321.
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Obesity and hypertension, which often coexist, are major risk factors for heart failure and are characterized by chronic, low-grade inflammation, which promotes adverse cardiac remodeling. While macrophages play a key role in cardiac remodeling, dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac injury. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation has been implicated in macrophage polarization. M1 macrophages primarily rely on glycolysis, whereas M2 macrophages rely on the tricarboxylic acid cycle and oxidative phosphorylation; thus, factors that affect macrophage metabolism may disrupt M1/M2 homeostasis and exacerbate inflammation. The mechanisms by which obesity and hypertension may synergistically induce macrophage metabolic dysfunction, particularly during cardiac remodeling, are not fully understood. We propose that obesity and hypertension induce M1 macrophage polarization via mechanisms that directly target macrophage metabolism, including changes in circulating glucose and fatty acid substrates, lipotoxicity, and tissue hypoxia. We discuss canonical and novel proinflammatory roles of macrophages during obesity-hypertension–induced cardiac injury, including diastolic dysfunction and impaired calcium handling. Finally, we discuss the current status of potential therapies to target macrophage metabolism during heart failure, including antidiabetic therapies, anti-inflammatory therapies, and novel immunometabolic agents.
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Keeling, Sara, Nadia Deashinta, Katherine M. Howard, Sara Vigil, Sheniz Moonie, and Barbara St Pierre Schneider. "Macrophage Colony Stimulating Factor-Induced Macrophage Differentiation Influences Myotube Elongation." Biological Research For Nursing 15, no. 1 (July 15, 2011): 62–70. http://dx.doi.org/10.1177/1099800411414871.
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Background: Unaccustomed exercise, high-intensity dynamic sports activities, or the resumption of normal weight-bearing after a period of disuse can induce skeletal muscle injury, which activates an inflammatory response followed by muscle regeneration. Specific subsets of macrophages are involved in muscle regeneration. But the exact role of macrophage differentiation during muscle regeneration remains to be elucidated. Objective: The objective of the study was to examine the effect of macrophage colony stimulating factor (M-CSF)-differentiated, lipopolysaccharides (LPS)-stimulated-macrophage-conditioned medium on muscle-cell proliferation, fusion, and elongation, which are key events during muscle regeneration and myogenesis. Method: Murine C2C12 myoblasts were cultured in conditioned medium obtained from PU5-1R macrophages that were (a) undifferentiated, unstimulated; (b) M-CSF-differentiated, unstimulated; (c) undifferentiated, LPS-stimulated; or (d) M-CSF-differentiated, LPS-stimulated. Myoblast proliferation ratio, nuclei number, and length were measured. Results: C2C12 cells cultured in conditioned medium from M-CSF-differentiated, LPS-stimulated macrophages had significantly more nuclei and greater length than cells cultured in conditioned medium from undifferentiated, LPS-stimulated macrophages. Dilution and denaturization of the M-CSF-differentiated, LPS-stimulated-macrophage medium prevented a marked increase in C2C12 nuclei number and length. However, the C2C12 myoblast proliferation ratio was significantly greater in conditioned medium from undifferentiated, LPS-stimulated macrophages than in conditioned medium from M-CSF-differentiated, LPS-stimulated macrophages. Conclusions: M-CSF-differentiated, LPS-stimulated macrophages may influence myogenesis and the early and terminal stages of muscle regeneration. This knowledge may aid in developing therapies that will directly expedite muscle repair and lead to faster rehabilitation and reduced rehabilitation costs.
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Randolph, Gwendalyn J. "Monocyte Trafficking, Inflammation, and Atherosclerosis." Blood 122, no. 21 (November 15, 2013): SCI—53—SCI—53. http://dx.doi.org/10.1182/blood.v122.21.sci-53.sci-53.
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Abstract Macrophages are central to the progression of atherosclerosis. An increased number of macrophages in plaque are associated with larger, more stenotic lesions. Furthermore, activated plaque macrophages promote rupture, the most significant clinical event affecting mortality. Plaque macrophages derive from monocytes that are recruited from blood. We have thus focused our efforts on understanding the mechanisms that regulate plaque macrophages, with emphasis on how macrophage-burden might be reduced to lower disease risk. We have developed techniques to discern whether macrophage contraction in plaques is due to emigration out of the plaque environment. Although this idea was our leading hypothesis, data obtained in a model of regression carried out in apoE-/- mice indicates that emigration of macrophages does not occur during regression. The idea was based on previous literature that monocyte-derived cells might be removed from sites of acute inflammation by emigrating to local lymph nodes. After finding that emigration of macrophages from resolving plaque in apoE-/- mice was poor, we revisited models of acute inflammation; in particular, thioglycollate-induced peritonitis, where emigration had been claimed to account for macrophage removal. New methodology to improve the quantification of macrophage loss from the peritoneum indicated that, like atherosclerosis, emigration of macrophages was a minor contributor to the contraction of macrophages associated with resolution. Instead, in both settings, macrophage loss was associated with a strong suppression of monocyte recruitment, coupled with ongoing macrophage apoptosis. These data strongly suggest that methods to block monocyte recruitment may provide a viable approach to reversing atherosclerosis. Current efforts focus on integrating the role of monocyte recruitment with local proliferation of macrophages in plaques, investigating macrophage motility in plaques during different disease states, and evaluating contraction of macrophages from plaques using other models of disease regression. Disclosures: No relevant conflicts of interest to declare.
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Snarski, Patricia, Sergiy Sukhanov, Tadashi Yoshida, Yusuke Higashi, Svitlana Danchuk, Bysani Chandrasekar, Di Tian, Vikara Rivera-Lopez, and Patrick Delafontaine. "Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 2 (February 2022): 113–26. http://dx.doi.org/10.1161/atvbaha.121.316090.
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Objective: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe −/ − (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe − / − background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1–derived peritoneal macrophages. Conclusions: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.
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García-Rodas, Rocío, Fernando González-Camacho, Juan Luis Rodríguez-Tudela, Manuel Cuenca-Estrella, and Oscar Zaragoza. "The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing." Infection and Immunity 79, no. 6 (March 21, 2011): 2136–44. http://dx.doi.org/10.1128/iai.00044-11.
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ABSTRACTCandida kruseiis a fungal pathogen of interest for the scientific community for its intrinsic resistance to fluconazole. Little is known about the interaction of this yeast with host immune cells. In this work, we have characterized the outcome of the interaction betweenC. kruseiand murine macrophages. OnceC. kruseiwas internalized, we observed different phenomena. In a macrophage-like cell line,C. kruseisurvived in a significant number of macrophages and induced filamentation and macrophage explosion. Phagocytosis ofC. kruseiled to actin polymerization around the yeast cells at the site of entry. Fluorescent specific staining with anti-Lamp1 and LysoTracker indicated that after fungal internalization, there was a phagolysosome maturation defect, a phenomenon that was more efficient when the macrophages phagocytosed killed yeast cells. Using cell line macrophages, we also observed macrophage fusion after cell division. When we used primary resident peritoneal macrophages in addition to macrophage explosion, we also observed a strong chemotaxis of uninfected macrophages to regions whereC. krusei-infected macrophages were present. We also noticed yeast transfer phenomena between infected macrophages. Primary macrophages inhibited pseudohypha elongation more efficiently than the macrophage-like cell line, suggesting thatC. kruseiinfection was better controlled by the former macrophages. Primary macrophages induced more tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) than the macrophage-like cell line. Our results demonstrate thatC. kruseican exploit the macrophages for replication, although other different outcomes are also possible, indicating that the interaction of this pathogen with phagocytic cells is very complex and regulated by multiple factors.
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Li, Xue, Deana Mikhalkova, Erhe Gao, Jin Zhang, Valerie Myers, Carmen Zincarelli, Yonghong Lei, et al. "Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 5 (November 2011): H1932—H1940. http://dx.doi.org/10.1152/ajpheart.00755.2010.
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Akt2 protein kinase has been shown to promote cell migration and actin polymerization in several cell types, including macrophages. Because migrating macrophages constitute an important inflammatory response after myocardial ischemia, we determined cardiac macrophage expression after ischemia-reperfusion (I/R) injury and cryo-injury in mice lacking Akt2 (Akt2-KO). At 7 days post-I/R, Akt2-KO cardiac tissues showed an increase in immunohistochemical staining for macrophage markers (Galectin 3 and F4/80) compared with wild-type (WT) mice, indicating macrophage density was increased in the injured Akt2-KO myocardium. This change was time dependent because macrophage density was similar between WT and Akt2-KO myocardium at 3 days post-I/R, but by 7 and 14 days post-I/R, macrophage density was significantly increased in Akt2-KO myocardium. Concomitantly, infarct size was larger and cardiac function was reduced in Akt2-KO mice subjected to I/R. However, when cryo-infarction produced similar infarct sizes in the anterior wall in both WT and Akt2-KO mice, macrophage density remained higher in Akt2-KO mouse myocardium, suggesting Akt2 regulates myocardial macrophage density independent of infarct size. Consistently, bone marrow from Akt2-KO mice enhanced myocardial macrophage density in both C57/B6 WT and Akt2-KO recipient mice. Finally, reciprocal ex-vivo coculturing of macrophages and cardiac myocytes showed that activated Akt2-KO peritoneal macrophages had reduced mobility and adhesion when compared with WT littermate controls. Thus, although Akt-2 KO mice did not affect the initial inflammation response after injury and Akt2 deficiency has been shown to impair cell migration or motility in macrophages, our data suggested a novel mechanism in which increasing retention of Akt2-KO macrophages resulted in increasing cardiac Akt2-KO macrophage density in the myocardial space.
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Pervin, Munmun, Mohammad Rabiul Karim, Mizuki Kuramochi, Takeshi Izawa, Mitsuru Kuwamura, and Jyoji Yamate. "Macrophage Populations and Expression of Regulatory Inflammatory Factors in Hepatic Macrophage-depleted Rat Livers under Lipopolysaccharide (LPS) Treatment." Toxicologic Pathology 46, no. 5 (June 24, 2018): 540–52. http://dx.doi.org/10.1177/0192623318776898.
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To investigate the significance of the appearance of hepatic macrophages and expression of inflammatory factors in normal and macrophage-depleted livers, hepatic macrophages were depleted with liposome (Lipo)-encapsulated clodronate (CLD; 50 mg/kg, i.v.) followed by lipopolysaccharide (LPS) administration (0.1 mg/kg, i.p.) in F344 rats (CLD + LPS). Vehicle control rats (Lipo + LPS) received empty-Lipo before LPS. The low dose of LPS did not result in microscopic changes in the liver in either treatment group but did modulate M1 and M2 macrophage activity in Lipo + LPS rats without altering repopulating hepatic macrophages in CLD + LPS rats. LPS treatment in Lipo + LPS rats dramatically increased the M1 (IL-1β, IL-6, TNF-α, and MCP-1) but not M2 macrophage-related factors (IL-4 and CSF-1) compared to CLD + LPS rats. In the CLD + LPS rats, the M2 macrophage-related factors IL-4 and CSF-1 were elevated. In conclusion, low-dose LPS activated hepatic macrophages in rat livers without causing liver injury or stimulating repopulating hepatic macrophages. These data suggest that LPS may alter the liver microenvironment by modulating M1 or M2 macrophage-related inflammatory mediators and macrophage-based hepatotoxicity.
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Gilbreath, M. J., C. A. Nacy, D. L. Hoover, C. R. Alving, G. M. Swartz, and M. S. Meltzer. "Macrophage activation for microbicidal activity against Leishmania major: inhibition of lymphokine activation by phosphatidylcholine-phosphatidylserine liposomes." Journal of Immunology 134, no. 5 (May 1, 1985): 3420–25. http://dx.doi.org/10.4049/jimmunol.134.5.3420.
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Abstract Resident peritoneal macrophages from untreated mice develop microbicidal activity against amastigotes of the protozoan parasite Leishmania tropica (current nomenclature = Leishmania major) after in vitro exposure to LK from antigen-stimulated leukocyte culture fluids. This LK-induced macrophage microbicidal activity was completely abrogated by addition of 7:3 phosphatidylcholine: phosphatidylserine liposomes. Liposome inhibition was not due to direct toxic effects against the parasite or macrophage effector cell; factors in LK that induce macrophage microbicidal activity were not adsorbed or destroyed by liposome treatment. Other phagocytic particles, such as latex beads, had no effect on microbicidal activity. Moreover, liposome inhibition of activated macrophage effector function was relatively selective: LK-induced macrophage tumoricidal activity was not affected by liposome treatment. Liposome inhibition was dependent upon liposome dose (5 nmoles/culture) and time of addition of leishmania-infected, LK-treated macrophage cultures. Addition of liposomes through the initial 8 hr of culture completely inhibited LK-induced macrophage microbicidal activity; liposomes added after 16 hr had no effect. Similarly, microbicidal activity by macrophages activated in vivo by BCG or Corynebacterium parvum was not affected by liposome treatment. Liposome treatment also did not affect the increased resistance to infection induced in macrophages by LK. These data suggest that liposomes interfere with one or more early events in the induction of activated macrophages (macrophage-LK interaction) and not with the cytotoxic mechanism itself (parasite-macrophage interaction). These studies add to the growing body of data that implicate cell lipid in regulatory events controlling macrophage effector function.
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Rosa, L. F. B. P. Costa, Y. Cury, and R. Curi. "Hormonal control of macrophage function and glutamine metabolism." Biochemistry and Cell Biology 69, no. 4 (April 1, 1991): 309–12. http://dx.doi.org/10.1139/o91-047.
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Murine macrophages have been reported to utilize glutamine at high rates. However, the role of glutamine in macrophage function is still unknown. In the present study, the maximum glutaminase activity of macrophages was investigated under several endocrine dysfunctions that are known to cause alterations in macrophage function. The results obtained suggest that glutamine might play an important role in the onset of phagocytosis in inflammatory macrophages. Moreover, the studies show that insulin, glucocorticoids, and thyroid hormones may be responsible for the regulation of glutamine metabolism and, consequently, of macrophage function.Key words: macrophage, glutamine, insulin, glucocorticoids, thyroid hormones, catecholamines.
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Martins, Flávia, Rosa Oliveira, Bruno Cavadas, Filipe Pinto, Ana Patrícia Cardoso, Flávia Castro, Bárbara Sousa, et al. "Hypoxia and Macrophages Act in Concert Towards a Beneficial Outcome in Colon Cancer." Cancers 12, no. 4 (March 28, 2020): 818. http://dx.doi.org/10.3390/cancers12040818.
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In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage–cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O2, followed by characterization of both cellular components. Different colon cancer patient cohorts were analyzed for hypoxia and immune markers, and their association with patient overall survival was established. A positive correlation between HIF1A and CD68 in colon cancer patients was identified but, unexpectedly, in cases with higher macrophage infiltration, HIF1A expression was associated with a better prognosis, in contrast to breast, gastric, and lung cancers. Under hypoxia, co-cultures’ secretome indicated a shift towards a pro-inflammatory phenotype. These alterations occurred along with increased macrophage phagocytic activity and decreased SIRPα expression. Cancer cells were more invasive and exhibited higher CD47 expression. We hypothesize that the better prognosis associated with HIF1AHighCD68High tumors could occur due to macrophagic pro-inflammatory pressure. Indeed, we found that tumors HIF1AHighCD68High expressed increased levels of CD8A, which is positively correlated with HIF1A. In conclusion, we show that in colon cancer, hypoxia drives macrophages into a pro-inflammatory phenotype, concomitant with increased infiltration of anti-tumor immune cells, favoring better disease outcome.
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Boutilier, Ava J., and Sherine F. Elsawa. "Macrophage Polarization States in the Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 13 (June 29, 2021): 6995. http://dx.doi.org/10.3390/ijms22136995.
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The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.
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Kim, Bo-Young, Ji Hyeon Ryu, Jisu Park, Byeongjun Ji, Hyun Soo Chun, Min Sun Kim, and Yong-Il Shin. "Fermented Lettuce Extract Induces Immune Responses through Polarization of Macrophages into the Pro-Inflammatory M1-Subtype." Nutrients 15, no. 12 (June 14, 2023): 2750. http://dx.doi.org/10.3390/nu15122750.
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It has been reported that lettuce and its bioactive compounds enhance the host immune system by acting as immune modulators. This study aimed to identify the immunological effect of fermented lettuce extract (FLE) on macrophages. To evaluate the efficacy of FLE in enhancing macrophage function, we measured and compared the levels of macrophage activation-related markers in FLE- and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Treatment with FLE activated RAW 264.7 macrophages, increased their phagocytic ability, and increased the production of nitric oxide (NO) and pro-inflammatory cytokine levels—similar to LPS. The effects of FLE on M1/M2 macrophage polarization were investigated by determining M1 and M2 macrophage transcript markers in mouse peritoneal macrophages. The FLE-related treatment of peritoneal macrophages enhanced the expression of M1 markers but reduced IL-4 treatment-induced M2 markers. After the generation of tumor-associated macrophages (TAMs), alterations in the levels of M1 and M2 macrophage markers were measured after treatment with FLE. The FLE-related treatment of TAMs increased the expression and production of pro-inflammatory cytokines and also led to the enhanced apoptosis of pancreatic cancer cells. These findings suggest that FLE may be useful for macrophage-targeted cancer therapy because of its ability to regulate the activation and polarization of macrophages in the tumor microenvironment.
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Hamrick, Terri S., Edward A. Havell, John R. Horton, and Paul E. Orndorff. "Host and Bacterial Factors Involved in the Innate Ability of Mouse Macrophages To Eliminate Internalized UnopsonizedEscherichia coli." Infection and Immunity 68, no. 1 (January 1, 2000): 125–32. http://dx.doi.org/10.1128/iai.68.1.125-132.2000.
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ABSTRACT In an effort to better understand genetic and cellular factors that influence innate immunity, we examined host and bacterial factors involved in the nonopsonic phagocytosis and killing ofEscherichia coli K-12 by mouse macrophages. Unelicited (resident) peritoneal macrophages from five different mouse strains, BALB/c, C57BL/6, CD-1, C3H/HeJ, and C3H/HeN, were employed. Additional macrophage populations were obtained from CD-1 mice (bone marrow-derived macrophages). Also, for BALB/c and C57BL/6 mice, peritoneal macrophages elicited with either thioglycolate or proteose peptone, bone marrow-derived macrophages, and macrophage-like cell lines derived from the two strains were employed. Two E. coli K-12 strains that differed specifically in their abilities to produce type 1 pili containing the adhesive protein FimH were examined. The parameters used to assess macrophage bacteriocidal activity were (i) the killing of internalized (gentamicin-protected)E. coli during the approximately 4-h assay and (ii) the initial rate at which internalized E. coli were eliminated. Data on these parameters allowed the following conclusions: (i) unelicited or proteose peptone-elicited peritoneal macrophages were significantly better at eliminating internalized bacteria than thioglycolate-elicited peritoneal macrophages, bone marrow-derived macrophages, or macrophage cell lines; (ii) the host genetic background had no significant effect upon the ability of unelicited peritoneal macrophages to kill E. coli (even though the mouse strains differ widely in their in vivo susceptibilities to bacterial infection); and (iii) the FimH phenotype had no significant effect uponE. coli survival once the bacterium was inside a macrophage. Additionally, there was no correlation between the bacteriocidal effectiveness of a macrophage population and the number of bacteria bound per macrophage. However, macrophage populations that were the least bacteriocidal tended to bind higher ratios of FimH+ to FimH− E. coli. The effect of gamma interferon, fetal calf serum, and the recombination proficiency of E. coli were examined as factors predicted to influence intracellular bacterial killing. These had no effect upon the rate of E. coli elimination by unelicited peritoneal macrophages.
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Saidah, Makfiyah, Beta Widya Oktiani, and Irham Taufiqurrahman. "THE EFFECT OF FLAVONOID PROPOLIS KELULUT (Trigona spp) EXTRACT ON MACROPHAGE CELL NUMBER IN PERIODONTITIS (IN VIVO STUDY IN MALE WISTAR RATE (Rattus novergicus) GINGIVA)." Dentino : Jurnal Kedokteran Gigi 5, no. 1 (March 12, 2020): 28. http://dx.doi.org/10.20527/dentino.v5i1.8117.
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Background : Periodontitis is a condition where there is an increase in the number of inflammatory cells, namely macrophages in periodontal tissue. Macrophag cell is 12-15μm in oval shape cell with purplish blue cytoplasm and this cell’s function is to phagocytes bacteria and infiltrate gingival tissue. Propolis kelulut contains flavonoid that have an anti-inflammatory effect by suppressing the signal pathway p38 MAPK, JNK 1/2 and NF-kB that it can reduce the number of macrophage cells in inflammatory periodontal tissues. Objective: The purpose of this study was to determine the effect of 0.5 mg dose flavonoid propolis extract on the number of macrophage cells in gingiva wistar rats that have been made into a periodontitis condition. Method: This study used a pure experimental method with a post test only with control group design. There were 9 treatment groups, including flavonoid propolis extract on 1,3,5 days, ibuprofen gel on 1,3,5 days and negative control on 1,3 dan 5 days. Results: There was an effect of giving 0.5 mg flavonoids propolis kelulut extract to the number of macrophage cells in periodontitis. Conclusion: Flavonoid propolis kelulut extract has an effect in increasing the number of macrophage cells on day 3 and decreasing the number of macrophage cells on the 5th day.
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Song, Lige, Garyfallia Papaioannou, Hengguang Zhao, Hilary F. Luderer, Christine Miller, Claudia Dall’Osso, Rosalynn M. Nazarian, Amy J. Wagers, and Marie B. Demay. "The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury." Endocrinology 157, no. 10 (August 15, 2016): 4066–75. http://dx.doi.org/10.1210/en.2016-1474.
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Ligand-dependent actions of the vitamin D receptor (VDR) play a pleiotropic role in the regulation of innate and adaptive immunity. The liganded VDR is required for recruitment of macrophages during the inflammatory phase of cutaneous wound healing. Although the number of macrophages in the granulation tissue 2 days after wounding is markedly reduced in VDR knockout (KO) compared with wild-type mice, VDR ablation does not alter macrophage polarization. Parabiosis studies demonstrate that circulatory chimerism with wild-type mice is unable to rescue the macrophage defect in the wounds of VDR KO mice and reveal that wound macrophages are of local origin, regardless of VDR status. Wound cytokine analyses demonstrated a decrease in macrophage colony-stimulating factor (M-CSF) protein levels in VDR KO mice. Consistent with this, induction of M-CSF gene expression by TGFβ and 1,25-dihydroxyvitamin D was impaired in dermal fibroblasts isolated from VDR KO mice. Because M-CSF is important for macrophage self-renewal, studies were performed to evaluate the response of tissue resident macrophages to this cytokine. A decrease in M-CSF induced proliferation and cyclin D1 expression was observed in peritoneal resident macrophages isolated from VDR KO mice, suggesting an intrinsic macrophage abnormality. Consistent with this, wound-healing assays in mice with macrophage-specific VDR ablation demonstrate that a normal wound microenvironment cannot compensate for the absence of the VDR in macrophages and thus confirm a critical role for the macrophage VDR in the inflammatory response to injury.
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Chen, Peiwen, Hao Zuo, Hu Xiong, Matthew J. Kolar, Qian Chu, Alan Saghatelian, Daniel J. Siegwart, and Yihong Wan. "Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis." Proceedings of the National Academy of Sciences 114, no. 3 (January 3, 2017): 580–85. http://dx.doi.org/10.1073/pnas.1614035114.
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Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor–macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor–macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.
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Li, Yingqiu, xiao yu, and Anlong Xu. "The p38-interacting protein negatively regulates monocyte/macrophage differentiation (HEM5P.239)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 120.19. http://dx.doi.org/10.4049/jimmunol.194.supp.120.19.
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Abstract Monocyte/macrophage differentiation is a central event in the immune response. Here, we investigated the role of p38IP (p38-interacting protein) in monocyte/macrophage differentiation. During monocyte/macrophage differentiation, we found that p38IP is downregulated. Forward knockdown of p38IP by RNA interference induced G1/S arrest, promoting monocytes differentiation into macrophages and the maturation of macrophages as well. Further analysis revealed that p38IP negatively regulates monocyte/macrophage differentiation. Moreover, we found that the downregulation of p38IP is caused by the upregulated miRNA during differentiation. Together, this study reveals the critical role and mechanism for p38IP in regulation of monocyte/macrophage differentiation.
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Singh, Gyanesh, U. C. Pachouri, Chirag Chopra, Preeti Bajaj, and Pushplata Singh. "Macrophage Gene Therapy: opening novel therapeutic avenues for immune disorders." F1000Research 4 (August 6, 2015): 495. http://dx.doi.org/10.12688/f1000research.6817.1.
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Macrophages are probably the most important cells of the mammalian immune system, and compromised macrophage function is known to cause several diseases. Their involvement in arthritis, cancer, infections, atherosclerosis, diabetes, and autoimmune disorders is well known. There has been a constantly growing need to transfer therapeutic genes into macrophages. Like most non-macrophage gene therapies,in vitrogene transfer has been attempted much more frequently in case of macrophages. However, primary macrophages are still somewhat recalcitrant to transfection. Macrophage-specific synthetic promoters, which were recently used successfully, can have up to 100-fold higher activity than that of native promoters. Adenovirus, lentivirus, and adeno-associated virus are commonly used for macrophage gene therapy. A number of non-viral methods are also popular for the transfer of exogenous DNA into macrophages. Gene transfer to macrophages using naked DNA has also been successful in a few cases. Macrophages have specific mechanisms to recognize and respond to bacterial DNA because of the presence of unmethylated CpG dinucleotides, which are rare in eukaryotic DNA. With interesting developments in this area, macrophage gene therapy appears to have great potential for immune therapies.
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Hardbower, Dana M., Mohammad Asim, Paula B. Luis, Kshipra Singh, Daniel P. Barry, Chunying Yang, Meredith A. Steeves, et al. "Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications." Proceedings of the National Academy of Sciences 114, no. 5 (January 17, 2017): E751—E760. http://dx.doi.org/10.1073/pnas.1614958114.
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Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during bothHelicobacter pyloriandCitrobacter rodentiuminfection. Myeloid-specificOdcdeletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function.Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.
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Ulndreaj, Antigona, Angela Li, Yonghong Chen, Rickvinder Besla, Shaun Pacheco, Marwan G. Althagafi, Myron I. Cybulsky, Thomas Lindsay, Clinton S. Robbins, and John S. Byrne. "Adventitial recruitment of Lyve-1− macrophages drives aortic aneurysm in an angiotensin-2-based murine model." Clinical Science 135, no. 10 (May 2021): 1295–309. http://dx.doi.org/10.1042/cs20200963.
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Abstract Objective: Aortic macrophage accumulation is characteristic of the pathogenesis of abdominal aortic aneurysm (AAA) but the mechanisms of macrophage accumulation and their phenotype are poorly understood. Lymphatic vessel endothelial receptor-1 (Lyve-1+) resident aortic macrophages independently self-renew and are functionally distinct from monocyte-derived macrophages recruited during inflammation. We hypothesized that Lyve-1+ and Lyve-1− macrophages differentially contribute to aortic aneurysm. Approach and results: Angiotensin-2 and β-aminopropionitrile (AT2/BAPN) were administered to induce AAA in C57BL/6J mice. Using immunohistochemistry (IHC), we demonstrated primarily adventitial accumulation of aortic macrophages, and in association with areas of elastin fragmentation and aortic dissection. Compared with controls, AAA was associated with a relative percent depletion of Lyve-1+ resident aortic macrophages and accumulation of Lyve-1− macrophages. Using CD45.1/CD45.2 parabiosis, we demonstrated aortic macrophage recruitment in AAA. Depletion of aortic macrophages in CCR2−/− mice was associated with reduced aortic dilatation indicating the functional role of recruitment from the bone marrow. Depletion of aortic macrophages using anti-macrophage colony-stimulating factor 1 receptor (MCSF1R)-neutralizing antibody (Ab) reduced the incidence of AAA. Conditional depletion of Lyve-1+ aortic macrophages was achieved by generating Lyve-1wt/cre Csf1rfl/fl mice. Selective depletion of Lyve-1+ aortic macrophages had no protective effects following AT2/BAPN administration and resulted in increased aortic dilatation in the suprarenal aorta. Conclusions: Aortic macrophage accumulation in AAA derives from adventitial recruitment of Lyve-1− macrophages, with relative percent depletion of Lyve-1+ macrophages. Selective targeting of macrophage subtypes represents a potential novel therapeutic avenue for the medical treatment of AAA.
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Bauerle, Kevin Thomas, Jisu Oh, Amy Elizabeth Riek, Adriana Dusso, Anabel L. Castro-Grattoni, R. Ariel Gomez, Maria L. Sequeira-Lopez, and Carlos Bernal-Mizrachi. "Vitamin D Deficiency Induces Macrophage Pro-Inflammatory Phenotype via ER Stress-Mediated Activation of Renin-Angiotensin System." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A304—A305. http://dx.doi.org/10.1210/jendso/bvab048.620.
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Abstract Chronic inflammation and local activation of the renin-angiotensin-aldosterone system (RAAS) play a pivotal role in the pathogenesis and progression of diabetic complications. In patients with type 2 diabetes (T2DM), the prevalence of vitamin D deficiency is almost twice that of non-diabetics, and vitamin d deficiency nearly doubles the risk of developing hypertension and cardiovascular complications compared to diabetics with normal vitamin D levels. Interestingly, mice lacking the vitamin D receptor (VDR) in macrophages (KODMAC) develop renin-dependent hypertension, insulin resistance, and inflammation via up-regulation of macrophage ER stress. Macrophages also express all major components of the RAAS system. However, little is known about the regulation of macrophage-generated renin and its role in modulating the sequelae of VDR signaling in macrophage function and cytokine production. This study found that KODMAC macrophages and vitamin D-deficient macrophages have increased expression and secretion of renin, angiotensin II, ACE, and AT1 receptor and that adhesion, migration, and cytokine release were also increased. Inhibition of ER stress in KODMAC macrophages and vitamin D-deficient macrophages with 4-Phenylbutyric acid (PBA) reduced RAS gene expression and macrophage pro-inflammatory phenotype. Renin 1c gene deletion decreased macrophage adhesion, migration, and cytokine release compared to macrophages with disrupted VDR signaling. Notably, disruption of VDR signaling induced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression in macrophages, and upregulation of renin expression in response to vitamin D deficiency was blunted in PCG1α-deficient macrophages. In conclusion, our findings delineate a mechanism by which impaired VDR signaling induces ER stress to drive PGC1α-dependent expression of renin and RAAS hyperactivation, thereby altering macrophage function and cytokine production. These data implicate RAAS as an essential mediator of VDR-mediated macrophage function and support ongoing investigations of VDR and RAAS modulation as therapeutic approaches in the management of T2DM and its complications.
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Ghanta, Swapna, Daniel A. Cuzzone, Jeremy S. Torrisi, Nicholas J. Albano, Walter J. Joseph, Ira L. Savetsky, Jason C. Gardenier, David Chang, Jamie C. Zampell, and Babak J. Mehrara. "Regulation of inflammation and fibrosis by macrophages in lymphedema." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 9 (May 1, 2015): H1065—H1077. http://dx.doi.org/10.1152/ajpheart.00598.2014.
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Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b-diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4+ cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4+ cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function.
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Cui, Jiong, Xiaoting Wu, Yankun Song, Yi Chen, and Jianxin Wan. "Complement C3 exacerbates renal interstitial fibrosis by facilitating the M1 macrophage phenotype in a mouse model of unilateral ureteral obstruction." American Journal of Physiology-Renal Physiology 317, no. 5 (November 1, 2019): F1171—F1182. http://dx.doi.org/10.1152/ajprenal.00165.2019.
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The impact of the renal microenvironment on macrophage phenotype determination can contribute to the progression or resolution of renal fibrosis. Although the complement proteins affect macrophage polarization, whether complement component 3 (C3) can induce macrophage polarization and regulate renal interstitial fibrosis remains undetermined. In the present study, we investigated the contribution of C3 on macrophage polarization and renal fibrosis in C3-deficient mice with unilateral ureteral obstruction and bone marrow-derived macrophages. C3-deficient mice exhibited attenuated renal fibrosis and ameliorated peritubular capillary rarefaction. Lack of C3 contributed to M2 macrophage polarization, increased IL-10 and VEGF164, and decreased TNF-α and soluble VEGF receptor 1 expression in the obstructed kidneys at the early stages of unilateral ureteral obstruction. C3a facilitated LPS-induced M1 polarization and inflammatory factor production in bone marrow-derived macrophages in vitro, accompanied by increased ERK, NF-κB, and STAT1 phosphorylation. The ERK-specific inhibitor PD98059 inhibited the phosphorylation of ERK, NF-κB, and STAT1 and attenuated M1 polarization-related inflammatory factor production. Furthermore, the culture supernatant from M1 macrophages and C3a-treated M2 macrophages were more detrimental to angiogenesis compared with M2 macrophage supernatants. Thus, complement C3 exacerbates renal interstitial fibrosis by facilitating macrophage M1 polarization, promoting proinflammatory cytokine expression, and deteriorating peritubular capillary rarefaction in the kidney.
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Yadav, Mahesh, and Jeffrey S. Schorey. "The β-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria." Blood 108, no. 9 (November 1, 2006): 3168–75. http://dx.doi.org/10.1182/blood-2006-05-024406.
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AbstractPattern recognition receptors (PRRs) play an essential role in a macrophage's response to mycobacterial infections. However, how these receptors work in concert to promote this macrophage response remains unclear. In this study, we used bone marrow–derived macrophages isolated from mannose receptor (MR), complement receptor 3 (CR3), MyD88, Toll-like receptor 4 (TLR4), and TLR2 knockout mice to examine the significance of these receptors in mediating a macrophage's response to a mycobacterial infection. We determined that mitogen-activated protein kinase (MAPK) activation and tumor necrosis factor-α (TNF-α) production in macrophage infected with Mycobacterium avium or M smegmatis is dependent on myeloid differentiation factor 88 (MyD88) and TLR2 but not TLR4, MR, or CR3. Interestingly, the TLR2-mediated production of TNF-α by macrophages infected with M smegmatis required the β-glucan receptor dectin-1. A similar requirement for dectin-1 in TNF-α production was observed for macrophages infected with M bovis Bacillus Calmette-Guerin (BCG), M phlei, M avium 2151-rough, and M tuberculosis H37Ra. The limited production of TNF-α by virulent M avium 724 and M tuberculosis H37Rv was not dependent on dectin-1. Furthermore, dectin-1 facilitated interleukin-6 (IL-6), RANTES (regulated on activation, normal T expressed and secreted), and granulocyte colony-stimulating factor (G-CSF) production by mycobacteria-infected macrophages. These are the first results to establish a significant role for dectin-1, in cooperation with TLR2, to activate a macrophage's proinflammatory response to a mycobacterial infection.