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1
Wen, Zhifa, Hongxiang Liu, Meng Zhou, and Li-xin Wang. "Tumor released autophagosomes regulate M2-like macrophage polarization (TUM6P.974)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 141.22. http://dx.doi.org/10.4049/jimmunol.194.supp.141.22.
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Abstract Tumor cells secrete mediators that modulate macrophage activation and polarization into M2 type tumor associated macrophages (TAMs), which contribute to tumor progression. However, the mechanisms that regulate the polarization are poorly defined. We have previously reported that the enrichment of autophagosomes in tumor cell conditioned medium and malignant ascites from patients. The present study investigated the hypothesis that tumor released autophagosomes promoted M2 polarization. Here we isolated autophagosomes released from murine liver cancer cells using affinity purification. In vivo mouse experiments demonstrated that intraperitoneal injected autophagosomes were efficiently internalized by peritoneal macrophages, which correlated with upregulation of M2 markers. In vitro, coculture of autophagosomes with bone marrow-derived macrophages (BMDMs) also induced macrophage polarization into a M2-like phenotype. Furthmore, this effect of autophagosomes was largely abolished in BMDMs from MyD88 KO mice. Taken together, our findings suggest that, under stress conditions, tumor released autophagosomes may promote tumor progression via regulation of TAMs in tumor microenvironment, providing new insight into TAMs polarization. Keywords: Tumor released autophagosomes, Macrophage, Polarization, MyD88.
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Draijer, Christina, Patricia Robbe, Carian E. Boorsma, Machteld N. Hylkema, and Barbro N. Melgert. "Characterization of Macrophage Phenotypes in Three Murine Models of House-Dust-Mite-Induced Asthma." Mediators of Inflammation 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/632049.
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In asthma, an important role for innate immunity is increasingly being recognized. Key innate immune cells in the lungs are macrophages. Depending on the signals they receive, macrophages can at least have an M1, M2, or M2-like phenotype. It is unknown how these macrophage phenotypes behave with regard to (the severity of) asthma. We have quantified the phenotypes in three models of house dust mite (HDM-)induced asthma (14, 21, and 24 days). M1, M2, and M2-like phenotypes were identified by interferon regulatory factor 5 (IRF5), YM1, and IL-10, respectively. We found higher percentages of eosinophils in HDM-exposed mice compared to control but no differences between HDM models. T cell numbers were higher after HDM exposure and were the highest in the 24-day HDM protocol. Higher numbers of M2 macrophages after HDM correlated with higher eosinophil numbers. In mice with less severe asthma, M1 macrophage numbers were higher and correlated negatively with M2 macrophages numbers. Lower numbers of M2-like macrophages were found after HDM exposure and these correlated negatively with M2 macrophages. The balance between macrophage phenotypes changes as the severity of allergic airway inflammation increases. Influencing this imbalanced relationship could be a novel approach to treat asthma.
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Lalor, Richard, and Sandra O’Neill. "Bovine κ-Casein Fragment Induces Hypo-Responsive M2-Like Macrophage Phenotype." Nutrients 11, no. 7 (July 23, 2019): 1688. http://dx.doi.org/10.3390/nu11071688.
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Immunomodulatory nutraceuticals have garnered special attention due to their therapeutic potential for the amelioration of many chronic inflammatory conditions. Macrophages are key players in the induction, propagation and resolution of inflammation, actively contributing to the pathogenesis and resolution of inflammatory disorders. As such, this study aimed to investigate the possible therapeutic effects bovine casein derived nutraceuticals exert on macrophage immunological function. Initial studies demonstrated that sodium caseinate induced a M2-like macrophage phenotype that was attributed to the kappa-casein subunit. Kappa-casein primed macrophages acquired a M2-like phenotype that expressed CD206, CD54, OX40L, CD40 on the cell surface and gene expression of Arg-1, RELM-α and YM1, archetypical M2 markers. Macrophages stimulated with kappa-casein secreted significantly reduced TNF-α and IL-10 in response to TLR stimulation through a mechanism that targeted the nuclear factor-κB signal transduction pathway. Macrophage proteolytic processing of kappa-casein was required to elicit these suppressive effects, indicating that a fragment other than C-terminal fragment, glycomacropeptide, induced these modulatory effects. Kappa-casein treated macrophages also impaired T-cell responses. Given the powerful immuno-modulatory effects exhibited by kappa-casein and our understanding of immunopathology associated with inflammatory diseases, this fragment has the potential as an oral nutraceutical and therefore warrants further investigation.
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Lyu, Qingkang, Edwin J. A. Veldhuizen, Irene S. Ludwig, Victor P. M. G. Rutten, Willem van Eden, Alice J. A. M. Sijts, and Femke Broere. "Characterization of polarization states of canine monocyte derived macrophages." PLOS ONE 18, no. 11 (November 8, 2023): e0292757. http://dx.doi.org/10.1371/journal.pone.0292757.
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Macrophages can reversibly polarize into multiple functional subsets depending on their micro-environment. Identification and understanding the functionality of these subsets is relevant for the study of immune‑related diseases. However, knowledge about canine macrophage polarization is still in its infancy. In this study, we polarized canine monocytes using GM-CSF/IFN- γ and LPS towards M1 macrophages or M-CSF and IL-4 towards M2 macrophages and compared them to undifferentiated monocytes (M0). Polarized M1 and M2 macrophages were thoroughly characterized for morphology, surface marker features, gene profiles and functional properties. Our results showed that canine M1-polarized macrophages obtained a characteristic large, roundish, or amoeboid shape, while M2-polarized macrophages were smaller and adopted an elongated spindle-like morphology. Phenotypically, all macrophage subsets expressed the pan-macrophage markers CD14 and CD11b. M1-polarized macrophages expressed increased levels of CD40, CD80 CD86 and MHC II, while a significant increase in the expression levels of CD206, CD209, and CD163 was observed in M2-polarized macrophages. RNAseq of the three macrophage subsets showed distinct gene expression profiles, which are closely associated with immune responsiveness, cell differentiation and phagocytosis. However, the complexity of the gene expression patterns makes it difficult to assign clear new polarization markers. Functionally, undifferentiated -monocytes, and M1- and M2- like subsets of canine macrophages can all phagocytose latex beads. M2-polarized macrophages exhibited the strongest phagocytic capacity compared to undifferentiated monocytes- and M1-polarized cells. Taken together, this study showed that canine M1 and M2-like macrophages have distinct features largely in parallel to those of well-studied species, such as human, mouse and pig. These findings enable future use of monocyte derived polarized macrophages particularly in studies of immune related diseases in dogs.
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Sánchez-Reyes, Karina, Alejandro Bravo-Cuellar, Georgina Hernández-Flores, José Manuel Lerma-Díaz, Luis Felipe Jave-Suárez, Paulina Gómez-Lomelí, Ruth de Celis, Adriana Aguilar-Lemarroy, Jorge Ramiro Domínguez-Rodríguez, and Pablo Cesar Ortiz-Lazareno. "Cervical Cancer Cell Supernatants Induce a Phenotypic Switch from U937-Derived Macrophage-Activated M1 State into M2-Like Suppressor Phenotype with Change in Toll-Like Receptor Profile." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/683068.
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Cervical cancer (CC) is the second most common cancer among women worldwide. Infection with human papillomavirus (HPV) is the main risk factor for developing CC. Macrophages are important immune effector cells; they can be differentiated into two phenotypes, identified as M1 (classically activated) and M2 (alternatively activated). Macrophage polarization exerts profound effects on the Toll-like receptor (TLR) profile. In this study, we evaluated whether the supernatant of human CC cells HeLa, SiHa, and C-33A induces a shift of M1 macrophage toward M2 macrophage in U937-derived macrophages.Results. The results showed that soluble factors secreted by CC cells induce a change in the immunophenotype of macrophages from macrophage M1 into macrophage M2. U937-derived macrophages M1 released proinflammatory cytokines and nitric oxide; however, when these cells were treated with the supernatant of CC cell lines, we observed a turnover of M1 toward M2. These cells increased CD163 and IL-10 expression. The expression of TLR-3, -7, and -9 is increased when the macrophages were treated with the supernatant of CC cells.Conclusions. Our result strongly suggests that CC cells may, through the secretion of soluble factors, induce a change of immunophenotype M1 into M2 macrophages.
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Zhu, Wenya, Qianqian Chen, Yi Li, Jun Wan, Jia Li, and Shuai Tang. "HIF-1α-Overexpressing Mesenchymal Stem Cells Attenuate Colitis by Regulating M1-like Macrophages Polarization toward M2-like Macrophages." Biomedicines 11, no. 3 (March 8, 2023): 825. http://dx.doi.org/10.3390/biomedicines11030825.
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A modified mesenchymal stem cell (MSC) transplantation is a highly effective and precise treatment for inflammatory bowel disease (IBD), with a significant curative effect. Thus, we aim to examine the efficacy of hypoxia-inducible factor (HIF)–1α-overexpressing MSC (HIF-MSC) transplantation in experimental colitis and investigate the immunity regulation mechanisms of HIF-MSC through macrophages. A chronic experimental colitis mouse model was established using 2,4,6-trinitrobenzene sulfonic acid. HIF-MSC transplantation significantly attenuated colitis in weight loss rate, disease activity index (DAI), colon length, and pathology score and effectively rebuilt the local and systemic immune balance. Macrophage depletion significantly impaired the benefits of HIF-MSCs on mice with colitis. Immunofluorescence analysis revealed that HIF-MSCs significantly decreased the number of M1-like macrophages and increased the number of M2-like macrophages in colon tissues. In vitro, co-culturing with HIF-MSCs significantly decreased the expression of pro-inflammatory factors, C-C chemokine receptor 7 (CCR-7), and inducible nitric oxide synthase (INOS) and increased the expression of anti-inflammatory factors and arginase I (Arg-1) in induced M1-like macrophages. Flow cytometry revealed that co-culturing with HIF-MSCs led to a decrease in the proportions of M1-like macrophages and an increase in that of M2-like macrophages. HIF-MSCs treatment notably upregulated the expression of downstream molecular targets of phosphatidylinositol 3-kinase-γ (PI3K-γ), including HIF-1α and p-AKT/AKT in the colon tissue. A selected PI3K-γ inhibitor, IPI549, attenuated these effects, as well as the effect on M2-like macrophage polarization and inflammatory cytokines in colitis mice. In vitro, HIF-MSCs notably upregulated the expression of C/EBPβ and AKT1/AKT2, and PI3K-γ inhibition blocked this effect. Modified MSCs stably overexpressed HIF-1α, which effectively regulated macrophage polarization through PI3K-γ. HIF-MSC transplantation may be a potentially effective precision therapy for IBD.
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Strizova, Zuzana, Iva Benesova, Robin Bartolini, Rene Novysedlak, Eva Cecrdlova, Lily Koumbas Foley, and Ilja Striz. "M1/M2 macrophages and their overlaps – myth or reality?" Clinical Science 137, no. 15 (August 2023): 1067–93. http://dx.doi.org/10.1042/cs20220531.
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Abstract Macrophages represent heterogeneous cell population with important roles in defence mechanisms and in homoeostasis. Tissue macrophages from diverse anatomical locations adopt distinct activation states. M1 and M2 macrophages are two polarized forms of mononuclear phagocyte in vitro differentiation with distinct phenotypic patterns and functional properties, but in vivo, there is a wide range of different macrophage phenotypes in between depending on the microenvironment and natural signals they receive. In human infections, pathogens use different strategies to combat macrophages and these strategies include shaping the macrophage polarization towards one or another phenotype. Macrophages infiltrating the tumours can affect the patient’s prognosis. M2 macrophages have been shown to promote tumour growth, while M1 macrophages provide both tumour-promoting and anti-tumour properties. In autoimmune diseases, both prolonged M1 activation, as well as altered M2 function can contribute to their onset and activity. In human atherosclerotic lesions, macrophages expressing both M1 and M2 profiles have been detected as one of the potential factors affecting occurrence of cardiovascular diseases. In allergic inflammation, T2 cytokines drive macrophage polarization towards M2 profiles, which promote airway inflammation and remodelling. M1 macrophages in transplantations seem to contribute to acute rejection, while M2 macrophages promote the fibrosis of the graft. The view of pro-inflammatory M1 macrophages and M2 macrophages suppressing inflammation seems to be an oversimplification because these cells exploit very high level of plasticity and represent a large scale of different immunophenotypes with overlapping properties. In this respect, it would be more precise to describe macrophages as M1-like and M2-like.
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Li, Dezhi, Min Yan, Fengfei Sun, Junmei Song, Xingsheng Hu, Sijia Yu, Lina Tang, and Shishan Deng. "miR-498 inhibits autophagy and M2-like polarization of tumor-associated macrophages in esophageal cancer via MDM2/ATF3." Epigenomics 13, no. 13 (July 2021): 1013–30. http://dx.doi.org/10.2217/epi-2020-0341.
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Structured abstract Aim: To elucidate the effect of miRNA (miR)-498 on autophagy and M2-like macrophage polarization in esophageal cancer. Methods: Autophagy was evaluated in esophageal cancer. Macrophage markers specific for M1- or M2-like phenotype were determined. The binding relationships between miR-498 and MDM2, MDM2 and ATF3 were analyzed. Results: miR-498 was downregulated in esophageal cancer and was associated with disease-free and overall patient survival. Enhanced miR-498 reduced LC3I conversion to LC3II and increased p62 accumulation in KYSE-150 cells, and increased macrophage polarization to M2-like phenotype in KYSE-150 and TAM co-culture. miR-498 inhibited MDM2-mediated ATF3 degradation, thus suppressing autophagy and M2-like polarization of macrophages in esophageal cancer. Conclusion: miR-498 may inhibit autophagy and M2-like polarization of macrophages to suppress esophageal cancer via MDM2/ATF3.
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Ronaghan, Natalie J., Mandy Soo, Uriel Pena, Marisa Tellis, Wenming Duan, Nooshin Tabatabaei-Zavareh, Philipp Kramer, Juan Hou, and Theo J. Moraes. "M1-like, but not M0- or M2-like, macrophages, reduce RSV infection of primary bronchial epithelial cells in a media-dependent fashion." PLOS ONE 17, no. 10 (October 13, 2022): e0276013. http://dx.doi.org/10.1371/journal.pone.0276013.
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Respiratory syncytial virus (RSV) is a common childhood infection that in young infants can progress into severe bronchiolitis and pneumonia. Disease pathogenesis results from both viral mediated and host immune processes of which alveolar macrophages play an important part. Here, we investigated the role of different types of alveolar macrophages on RSV infection using an in vitro co-culture model involving primary tissue-derived human bronchial epithelial cells (HBECs) and human blood monocyte-derived M0-like, M1-like, or M2-like macrophages. It was hypothesized that the in vitro model would recapitulate previous in vivo findings of a protective effect of macrophages against RSV infection. It was found that macrophages maintained their phenotype for the 72-hour co-culture time period and the bronchial epithelial cells were unaffected by the macrophage media. HBEC infection with RSV was decreased by M1-like macrophages but enhanced by M0- or M2-like macrophages. The medium used during the co-culture also impacted the outcome of the infection. This work demonstrates that alveolar macrophage phenotypes may have differential roles during epithelial RSV infection, and demonstrates that an in vitro co-culture model could be used to further investigate the roles of macrophages during bronchial viral infection.
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Di Martile, Marta, Valentina Farini, Francesca Maria Consonni, Daniela Trisciuoglio, Marianna Desideri, Elisabetta Valentini, Simona D'Aguanno, et al. "Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages." Journal for ImmunoTherapy of Cancer 8, no. 1 (April 2020): e000489. http://dx.doi.org/10.1136/jitc-2019-000489.
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BackgroundA bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.MethodsTHP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.ResultsHigher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+and CD8+IFNγ+effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.ConclusionsTaken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.
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Shao, Xia, Boting Wu, Pu Chen, Yanxia Zhan, Feng Li, Fanli Hua, Lihua Sun, and Yunfeng Cheng. "The Role of M2 Macrophage in Primary Immune Thrombocytopenia." Blood 134, Supplement_1 (November 13, 2019): 2355. http://dx.doi.org/10.1182/blood-2019-129667.
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Background: Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disorder, characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Although impaired T cells have been implicated to participate in the pathogenesis of ITP, another immune cell signified as M2 macrophages has not been investigated properly in ITP patients. This study aimed to investigate the role of M2 macrophage subsets in primary immune thrombocytopenia (ITP). Methods: Peripheral blood mononuclear cells (PBMC) from newly diagnosed ITP patients and healthy controls (HC) were isolated. M2-like macrophages (CD68+CD163+) and M2 macrophages (CX3CR1+CD163+) were measured by flow cytometry. The correlation between CD68+CD163+ cells and CX3CR1+CD163+ cells was also analyzed. The CX3CR1+cells were sorted by magnetic bead, CD68+CD163+ in PBMC of ITP patients and healthy controls were then isolated, and the proportion of m2-like macrophages before and after the sorting was analyzed. The PPAR gamma and arg-1 levels of mRNAs and proteins of CX3CR1+ M2 macrophages were examined by Real-time PCR and Western Blot, respectively. Results: CX3CR1+CD163+M2 macrophages were positively correlated with CD68+ CD163+ M2-like macrophages in ITP patients (r = 0.54, p < 0.01). After magnetic bead separation, the proportion of CD68+CD163+ cells in CX3CR1+ cells was significantly increased (p = 0.02). Compared with HC, both the mRNA and protein levels of arg-1 of CX3CR1+ M2 macrophages were significantly increased in patients with ITP. The expression level of PPAR gamma protein was significantly increased in ITP than that of HC. However no statistical difference was detected at mRNA expression level, although it was numerically higher in ITP patients than in HC ( p = 0.19). Conclusion: The peripheral CX3CR1+ M2 macrophage exercises similar phenotypes and functions of M2 macrophage. The remarkably increased expression of arg-1 at both transcription and protein levels and PPAR gamma at protein level of CX3CR1+M2 macrophages in ITP patients suggests potential immunomodulatory functions of these macrophage subsets during ITP pathogenesis. However, no significant change at mRNA level of PPAR gamma indicating that the increased PPAR gamma protein level might be caused by other mechanisms, such as after transcription abnormalities, which warrants further investigation. Disclosures No relevant conflicts of interest to declare.
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Vicenzi, Silvia, Trung Tran, Lara Avsharian, Joshua Hartman, Anna Rapp, and Leslie Crews. "Tuning the Innate Immune Multiple Myeloma Microenvironment By Modulating IRF4." Blood 142, Supplement 1 (November 28, 2023): 6604. http://dx.doi.org/10.1182/blood-2023-187814.
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The tumor microenvironment (TME) has emerged as a key contributor to cancer progression in numerous solid tumors as well as blood cancers that evolve in the bone marrow (BM). In the context of multiple myeloma (MM), survival of malignant plasma cells is supported by interactions with the BM microenvironment, which is comprised of various components including cells, extracellular matrix, and soluble factors. Therefore, the development of strategies that specifically target the MM BM microenvironment is crucial for improving current disease prognosis. Within the BM niche, M2-like myeloma-associated macrophages (MAMs) play a significant role in cancer cell survival and progression and have been implicated in producing an immune-suppressive TME by generating inflammatory mediators, growth factors, cytokines, chemokines, etc. Macrophages exhibit plasticity with regard to their polarization state, which enable them to dynamically respond and adapt to different environmental stimuli in order to fulfill important immune functions. Thus, the reprogramming of M2-like, pro-tumoral MAMs toward a M1-like, anti-tumoral phenotype represents a promising therapeutic strategy. In MM, inflammatory and anti-viral pathways promote disease progression. Interferon regulatory factor 4 (IRF4) is a transcription factor that has previously been shown to promote MM progression through enhanced survival of malignant plasma cells. Under physiological conditions, IRF4 also regulates macrophage polarization, where its expression drives alternative activation of macrophages primarily to M2-like (anti-inflammatory) phenotypes. However, the extent to which IRF4 activation or direct inhibition governs the polarization status and pro-tumoral activity of macrophages in the MM microenvironment has not been fully elucidated. In this study, we sought to further explore the role of IRF4 in macrophage polarization and investigated the potential of modulating IRF4 expression to reprogram myeloma-associated macrophages (MAMs) as a novel therapeutic strategy. First, we developed myeloma-tailored macrophage polarization models using primary human peripheral blood-derived monocytes and the THP1 monocyte cell line. Our M1 and M2 polarization models utilize a customized cocktail of myeloid growth factors and cytokines, supplemented with interleukin (IL)-6 to mimic the IL-6-enriched MM microenvironment. Characterization of M1 (CD80, TNFα, and CXCL10) and M2 (MRC1, FN1, and CCL22) markers confirmed the presence of distinct macrophage subpopulations, as well as upregulated expression of IRF4 in M2-like progeny and IRF5 in M1-like macrophages. To investigate the extent to which IRF4 activation or direct inhibition governs macrophage polarization and function, overexpression and knockdown experiments on macrophages were performed in vitro, along with whole transcriptome sequencing of IRF4-overexpressing THP1 monocytes compared to vector-transduced controls. Gene expression analyses revealed that genetic down-modulation of IRF4 in M2-like macrophages shifts the polarization status toward a hybrid phenotype that displays enhanced M1-like properties, while still retaining M2-like characteristics. This shift in polarization state was further amplified when monocytes were transduced to overexpress IRF4 prior to differentiation into M2-like macrophages and subsequent IRF4 knockdown, suggesting that IRF4 plays a key regulatory role in tuning macrophage polarization. Taken together, our preclinical findings provide groundwork for future studies on MAMs and suggest that an IRF4-mediated macrophage reprogramming strategy is a promising therapeutic approach for patients with MM and a variety of other malignancies typified by an anti-inflammatory TME.
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Laskar, Amit, Jonas Eilertsen, Wei Li, and Xi-Ming Yuan. "SPION primes THP1 derived M2 macrophages towards M1-like macrophages." Biochemical and Biophysical Research Communications 441, no. 4 (November 2013): 737–42. http://dx.doi.org/10.1016/j.bbrc.2013.10.115.
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Kumar, Sudhir, Sonam Mittal, Prachi Gupta, Mona Singh, Pradeep Chaluvally-Raghavan, and Sunila Pradeep. "Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment." Cancers 14, no. 21 (October 25, 2022): 5224. http://dx.doi.org/10.3390/cancers14215224.
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The interaction between tumor cells and macrophages in the tumor microenvironment plays an essential role in metabolic changes in macrophages and reprograms them towards a pro-tumorigenic phenotype. Increasing evidence indicates that macrophage metabolism is a highly complex process and may not be as simple as previously thought. Pro-inflammatory stimuli switch macrophages towards an M1-like phenotype and rely mainly on aerobic glycolysis and fatty acid synthesis, whereas anti-inflammatory stimuli switch macrophages towards an M2-like phenotype. M2-like macrophages depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation. However, this metabolically reprogrammed phenotypic switch in macrophages remained a mystery for a while. Therefore, through this review, we tend to describe how macrophage immunometabolism determines macrophage phenotypes and functions in tumor microenvironments (TMEs). Furthermore, we have discussed how metabolic reprogramming in TAM can be used for therapeutic intervention and drug resistance in ovarian cancer.
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Gong, Xiaocheng, Yunfei Liu, Keying Liang, Zixi Chen, Ke Ding, Li Qiu, Jinfen Wei, and Hongli Du. "Cucurbitacin I Reverses Tumor-Associated Macrophage Polarization to Affect Cancer Cell Metastasis." International Journal of Molecular Sciences 24, no. 21 (November 2, 2023): 15920. http://dx.doi.org/10.3390/ijms242115920.
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The tumor microenvironment plays a critical role in tumor progression and immune regulation. As one of the most important components of the tumor microenvironment, macrophages have become a new therapeutic target for inhibiting tumor progression. Despite the well-documented anticancer activity of cucurbitacin I, its effect on macrophages remains unclear. In this study, we established a coculture system of macrophages and cancer cells under hypoxic conditions to simulate the tumor-promoting environment mediated by M2-like macrophages. We determined whether cucurbitacin I modulates M2-like polarization in macrophages in vitro and conducted RNA sequencing to identify gene expression changes induced by cucurbitacin I in macrophages. The results indicated a remarkable inhibition of the M2-like polarization phenotype in macrophages following treatment with cucurbitacin I, which was accompanied by the significant downregulation of heme oxygenase-1. Moreover, we found that cucurbitacin I-treated macrophages reduced the migration of cancer cells by inhibiting the M2 polarization in vitro. These findings highlight the potential of cucurbitacin I as a therapeutic agent that targets M2-like macrophages to inhibit cancer cell metastasis. Our study provides novel insights into the intricate interplay among macrophage polarization, cucurbitacin I, and heme oxygenase-1, thereby opening new avenues for cancer treatment.
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Kuo, Chan-Yen, Tzu-Hsien Yang, Pei-Fang Tsai, and Chun-Hsien Yu. "Role of the Inflammatory Response of RAW 264.7 Cells in the Metastasis of Novel Cancer Stem-Like Cells." Medicina 57, no. 8 (July 30, 2021): 778. http://dx.doi.org/10.3390/medicina57080778.
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Background and objectives: Tumor progression and the immune response are intricately linked. Additionally, the presence of macrophages in the microenvironment is essential for carcinogenesis, but regulation of the polarization of M1- and M2-like macrophages and their role in metastasis remain unclear. Based on previous studies, both reactive oxygen species (ROS) and the endoplasmic reticulum (ER) are emerging as key players in macrophage polarization. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, there is limited knowledge regarding how they affect the macrophage-dependent innate host defense. Materials and methods: We detected the levels of ROS, the ability of chemotaxis, the expressions of markers of M1-/M2-like macrophages in RAW264.7 in presence of T2- and T2C-conditioned medium. Results: The results of this study indicated that ROS levels were decreased in RAW 264.7 cells when cultured with T2C-conditioned medium, while there was an improvement in chemotaxis abilities. We also found that the M2-like macrophages were characterized by an elongated shape in RAW 264.7 cells cultured in T2C-conditioned medium, which had increased CD206 expression but decreased expression of CD86 and inducible nitric oxide synthase. Suppression of ER stress shifted polarized M1-like macrophages toward an M2-like phenotype in RAW 264.7 cells cultured in T2C-conditioned medium. Conclusions: Taken together, we conclude that the polarization of macrophages is associated with the alteration of cell shape, ROS accumulation, and ER stress.
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Myers, Kayla V., Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, and Kenneth J. Pienta. "Abstract 2546: Targeting MerTK-mediated efferocytosis in the prostate cancer TME." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2546. http://dx.doi.org/10.1158/1538-7445.am2022-2546.
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Abstract The prostate cancer tumor microenvironment (TME) is comprised of many different components and cell types that influence tumor progression and patient outcome. Macrophages are highly abundant immune cells in the prostate cancer TME. Macrophage phenotypes can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages) and most macrophages in the prostate cancer TME are M2-like. Efferocytosis, the phagocytosis of apoptotic cells, is a pro-tumor function of M2-like macrophages. We have developed a flow cytometry assay to quantify efferocytosis of the prostate cancer cell line LNCaP. With both cell line-based THP-1 macrophages and human monocyte-derived macrophages (HMDMs), we observe that M2 macrophages efferocytose LNCaP cells more than M1 macrophages. Based on literature from other models and contexts, efferocytosis further supports the M2-like phenotype. Efferocytosis also prevents the apoptotic cell from progressing to secondary necrosis, which would attract an M1-like macrophage phenotype. Due these aspects, we hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages. Following efferocytosis of LNCaP cells by M2 HMDMs, we detect a decrease in the M1-like, anti-tumor marker CD80 and an increase in M2-like, pro-tumor markers CD206 and PDL1. Due to this role in modulating macrophage phenotype, we hypothesize targeting efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate, including M1-like macrophages. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. At both the protein and mRNA level, we detect higher MerTK expression in M2 than M1 THP-1 macrophages and HMDMs. Upon addition of apoptotic LNCaP cells, we observe an increase in phosphorylated MerTK (active form), suggesting the role of MerTK in prostate cancer cell efferocytosis. Currently, we are targeting MerTK to block prostate cancer cell efferocytosis in vitro and in vivo. We have generated a Mertk-/-, Hi-Myc mouse model on the FVB/N background. This prostate cancer GEMM will be used to assess the role of MerTK across different stages of prostate cancer progression. We will be comparing tumor size and immune infiltration between Mertk+/+ and Mertk-/- Hi-Myc mice aged to 2 months, 6 months and 12 months. We predict that the Mertk-/- mice will have smaller tumors and an overall anti-tumor immune infiltrate compared to Mertk+/+ mice in this model due to lack of efferocytosis. Citation Format: Kayla V. Myers, Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, Kenneth J. Pienta. Targeting MerTK-mediated efferocytosis in the prostate cancer TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2546.
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Gunes, Emine Gulsen, Sung Hee Kil, Xiwei Wu, Chingyu Su, Zhen Han, Hanjun Qin, Ting-Fang He, et al. "Tnfα Promotes an Immunosuppressive Microenvironment in Cutaneous T Cell Lymphoma and Regulates PD-L1 Expression." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-141070.
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Background: Tumor-associated macrophages (TAMs) play a key role in cutaneous T cell lymphoma (CTCL) growth and neoplastic T cells escape immune surveillance via PD1-PD-L1 axis (Querfeld, C., et al., Blood 2019; Khodadoust, M.S., et al., J Clin Oncol, 2020). There remains a lack of knowledge about how cytokines regulate the mechanisms controlling tumor-growth and polarize the tumor microenvironment (TME). Methods and Results: To investigate PD-L1 and PD1 expression on TAMs and T cells in mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SS) patients, we performed multiplex immunofluorescence (IF) staining of lesional skin samples of MF patients that demonstrated co-localization of PD-L1 on CD163+ M2 macrophages and PD1 expression on CD4+ and CD8+ T cells. In addition, significant enrichment of CD14+ and CD16+/CD14dim CD163+ M2-like monocytes/macrophages with upregulated PD-L1 expression in SS patients compared to healthy donors (HDs) was found via FACS analysis. We also performed 30-plex Luminex cytokine assay on plasma samples, which showed significantly increased IL-6, IL-10, IFNγ and TNFα levels in plasma of MF/SS compared to HDs. To investigate whether polarization towards an M2-like macrophage phenotype with increased PD-L1 expression correlated with the cytokine expression from CTCL-TME, we cultured total PBMCs from HDs with conditioned media (CM) from well established CTCL cell lines MyLa and HuT78 and analyzed PD-L1 mRNA, total PD-L1 protein and PD-L1 surface expression on M2-like macrophages. Significantly increased expression of PD-L1 protein in total PBMCs, especially on CD14+ and CD16+/CD14dim M2-like macrophages was seen. To understand whether distinct cytokines are associated with PD-L1 upregulation on CD163+ M2-like populations, total PBMCs from HDs were stimulated with human recombinant IL-6, IL-10, IFNγ or TNFα. Antibody blocking studies were conducted by adding anti human IL-6, IL-10, IFNγ or TNFα to the cultures with CM. TNFα stimulation significantly increased the CD14+ M2-like subset, but did not affect CD16+/CD14dim M2-like subset. We observed increased PD-L1 expression on both M2-like populations with TNFα compared to other cytokines. In contrast, blockade of TNFα significantly decreased the CD14+ M2-like subset with reduced PD-L1 expression and increased CD16+/CD14dim M2-like cells with upregulated PD-L1 expression. To explore whether the STAT pathway regulates PD-L1 expression through cytokines from CTCL TME, we incubated total PBMCs from HDs in CM of MyLa and HuT78 cells with/without a pan-STAT inhibitor, and in media alone. Inhibition of STAT signaling decreased CD14+ M2-like macrophage population, but did not alter the CD16+/CD14dim M2-like population. In addition, pan-STAT inhibition significantly reduced surface expression of PD-L1 on both CD14+ and CD16+/CD14dim M2-like macrophages. The effects of cytokines on STAT signaling components in regulating PD-L1 expression were also investigated by FACS and immunoblots. TNFα blockade significantly downregulated PD-L1, but also pSTAT1, pSTAT3 and pNF-κB levels, illustrating the role of TNFα on STAT1, STAT3 and NF-κB pathways in conjunction with PD-L1 expression. Stimulation with TNFα increased pSTAT3 level in CD14+ M2-like macrophages, while it did not significantly change pSTAT3 in CD16+/CD14dim M2-like macrophages. Anti-TNFα reduced pSTAT3 levels in CD14+ M2-like macrophages, but profoundly increased PD-L1 in CD16+/CD14dim M2-like macrophages, which aligns with our data of increased PD-L1 expression on CD16+/CD14dim M2-like macrophages following TNFα blockade. Conclusion: We profiled immune alterations of monocyte/macrophages populations and PD-L1 expression in CTCL regulated by selected cytokines. Our results support the dominant role of TNFα in the CTCL microenvironment. Here we show that TNFα potentiates the immunosuppressive TME through macrophage polarization and STAT-mediated PD-L1 regulation. Our results identify potential targets for combination immunotherapy. Disclosures Zain: Seattle Genetics: Research Funding; Mundai Pharma: Research Funding; Kyowa Kirlin: Research Funding. Abdulla:Johnson Johnson: Research Funding; Mallinckrodt: Consultancy, Speakers Bureau. Rosen:Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Querfeld:Trillium: Consultancy; Stemline: Consultancy; Bioniz: Consultancy; Helsinn: Consultancy; Celgene: Research Funding; Kyowa Kirin: Consultancy; MiRagen: Consultancy.
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Schnellhardt, Sören, Ramona Erber, Maike Büttner-Herold, Marie-Charlotte Rosahl, Oliver J. Ott, Vratislav Strnad, Matthias W. Beckmann, et al. "Accelerated Partial Breast Irradiation: Macrophage Polarisation Shift Classification Identifies High-Risk Tumours in Early Hormone Receptor-Positive Breast Cancer." Cancers 12, no. 2 (February 14, 2020): 446. http://dx.doi.org/10.3390/cancers12020446.
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Studies have demonstrated correlations between accumulations of tumour-associated macrophages (TAMs), especially of M2-like phenotype, and increased mortality in advanced breast cancer. We investigated the prognostic potential of both main macrophage phenotypes in early hormone receptor-positive (HR+) breast cancer. The studied cohort of 136 patients participated in an institutional APBI phase II trial. Patient selection was characterized by HR+, small tumour size and no metastasis. Tissue microarrays from pre-RT resection samples were double stained for CD68/CD163 using immunohistochemistry. CD68+/CD163− cells were considered M1-like macrophages and CD68+/CD163+ was representative of M2-like macrophages. M1 and M2 macrophage densities were analysed semi-automatically in the stromal and intraepithelial tumour compartment. Low M1 and high M2 densities were strongly associated with decreased disease-free survival (DFS). Combined TAM phenotype densities were studied after defining a macrophage shift classification: M1-shifted (M1 high, M2 low) and non-shifted (M1 low, M2 low; M1 high, M2 high) tumours entailed a favourable outcome. In contrast, M2-shifted (M1 low, M2 high) TAM populations were associated with extremely reduced DFS. Thus, the full predictive potential of TAMs was revealed in a combined analysis of both phenotypes. The M2-shifted subgroup of tumours is classified as high-risk and probably not suitable for partial breast irradiation.
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Yang, Jing, Chengxian Xu, Joseph Lechner, Haley Walls, and Kai Yang. "LKB1 regulates macrophage metabolism and functional polarization in immunomodulation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 168.14. http://dx.doi.org/10.4049/jimmunol.210.supp.168.14.
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Abstract Macrophages play critical roles in maintaining tissue homeostasis and modulating immune responses. In response to microenvironmental cytokines, macrophages coordinate cellular signaling networks and diverse transcriptional programs to dictate their phenotypical and functional heterogeneity. For instance, LPS/IFNγ and IL-4 induce classically (M1) and alternatively (M2) activated macrophages, respectively. Remodeling cellular metabolism has been highlighted a key process underlying macrophage functional polarization. However, the precise mechanisms coordinating macrophage metabolism and polarization remain elusive. We report here that the kinase LKB1, a well-known negative regulator of mTOR signaling pathway, serves as a metabolic checkpoint that connects cellular metabolic reprogramming to functional polarization in macrophages. We found that genetic depletion of LKB1 in macrophages polarized their differentiation towards M2-like macrophages, characterized by enhanced expression of M2-associated markers, independently of mTOR and STAT6 signaling pathways. In contrast, loss of LKB1 had no substantial impact on M1-like macrophages. Moreover, LKB1-defienct macrophages orchestrated reprogramming of mitochondrial metabolism to facilitate M2 polarization and tumor immune evasion. Collectively, our studies establish a previously unappreciated role for LKB1 in connecting macrophage metabolism and functional polarization in modulating tumor immunity. This work was partially supported by the Herman B Wells Center and Riley Children’s Foundation.
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Janss, Thibaut J., Simon Lefevre, Martijn Vlaming, Johan Arnold, Ellen Boelen, and Sofie Pattijn. "Abstract 2120: In vitro suppressive bioassays using macrophages for the evaluation of immuno-oncology drug." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2120. http://dx.doi.org/10.1158/1538-7445.am2022-2120.
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Abstract Targeted activation of tumor infiltrating lymphocytes in the tumor microenvironment (TME) with so-called immune checkpoint inhibitors (ICIs) has resulted in the development of revolutionizing therapeutic anti-tumor strategies. A deepening understanding of the TME has followed in the ability to see beyond current immune checkpoint strategies. It becomes clear that players like Tumor Associated Macrophages (TAM) and Myeloid Derived Suppressor Cells (MDSC) play a significant role by downregulating anti-tumor responses. Their presence and roles in the TME open novel possibilities for modulation of the TME. To study these mechanisms, bioassays mimicking the suppressive activity of these cells on lymphocytes were developed. With regulatory functions in both innate and adaptive immune responses and different phenotypic profiles that classically are divided into M1-like and M2-like, macrophages undeniably represent important players in the TME. Where classically activated M1-like macrophages comprise immune effector cells with an inflammatory phenotype, alternatively activated M2-like macrophages display suppressive activities. Correspondingly, a variety of solid tumors are found to be enriched with these M2-like macrophages, suppressing anti-tumor immunity. The diverse roles of macrophage subtypes are still being explored and their phenotypic classification is likely more complex than the classical M1-like and M2-like. However, in vitro assays based on these 2 subtypes can be a first step to screen for the impact of test molecules on the phenotype and function of macrophages and their subsequent effect on lymphocytes. Using in vitro polarization and functional assays, the impact of test molecules on M1-like and M2-like macrophage generation and polarization can be assessed. The impact of test molecules on macrophage functionality can be further evaluated using a macrophage suppressive assay. Here the ability of test molecules to enhance the stimulating effect of M1-like macrophages or to reverse the suppressive effect of M2-like macrophages on lymphocytes can be evaluated by assessing their proliferation and cytokine production. Moreover, the potential stimulatory effect of test compounds on macrophages to perform Antibody-dependent cellular phagocytosis (ADCP) of tumor cells in co-culture assays could be another strategy to review therapeutic potential. Collectively, the development of novel bioassays contributes to a better understanding of the TME and thereby illuminates the steps required to elicit anti-tumor immune responses. It further aids the functional assessment of potential of new drugs, the design of clinical trials and the discovery of relevant biomarkers. Citation Format: Thibaut J. Janss, Simon Lefevre, Martijn Vlaming, Johan Arnold, Ellen Boelen, Sofie Pattijn. In vitro suppressive bioassays using macrophages for the evaluation of immuno-oncology drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2120.
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Chen, Li-Mei, Hong-Yu Tseng, Yen-An Chen, Aushia Tanzih Al Haq, Pai-An Hwang, and Hsin-Ling Hsu. "Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression." Cancers 12, no. 2 (February 12, 2020): 421. http://dx.doi.org/10.3390/cancers12020421.
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Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.
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Jo, Wol Soon, Sohi Kang, Soo Kyung Jeong, Min Ji Bae, Chang Geun Lee, Yeonghoon Son, Hae-June Lee, et al. "Low Dose Rate Radiation Regulates M2-like Macrophages in an Allergic Airway Inflammation Mouse Model." Dose-Response 20, no. 3 (July 2022): 155932582211173. http://dx.doi.org/10.1177/15593258221117349.
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We investigated the effects of low dose rate radiation (LDR) on M1 and M2 macrophages in an ovalbumin-induced mouse model of allergic airway inflammation and asthma. After exposure to LDR (1 Gy, 1.818 mGy/h) for 24 days, mice were euthanized and the changes in the number of M1 and M2 macrophages in the bronchoalveolar lavage fluid and lung, and M2-associated cytokine levels, were assessed. LDR treatment not only restored the M2-rich microenvironment but also ameliorated asthma-related progression in a macrophage-dependent manner. In an ovalbumin-induced mouse model, LDR treatment significantly inhibited M2, but not M1, macrophage infiltration. M2-specific changes in macrophage polarization during chronic lung disease reversed the positive effects of LDR. Moreover, the levels of cytokines, including chemokine (C-C motif) ligand (CCL) 24, CCL17, transforming growth factor beta 1, and matrix metalloproteinase-9, decreased in ovalbumin-sensitized/challenged mice upon exposure to LDR. Collectively, our results indicate that LDR exposure suppressed asthmatic progression, including mucin accumulation, inflammation, and Type 2 T helper (Th2) cytokine (interleukin (IL)-4 and IL-13) production. In conclusion, LDR exposure decreased Th2 cytokine secretion in M2 macrophages, resulting in a reduction in eosinophilic inflammation in ovalbumin-sensitized/challenged mice.
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Mazzoni, Mara, Giuseppe Mauro, Lucia Minoli, Loredana Cleris, Maria Chiara Anania, Tiziana Di Marco, Emanuela Minna, et al. "Senescent Thyrocytes, Similarly to Thyroid Tumor Cells, Elicit M2-like Macrophage Polarization In Vivo." Biology 10, no. 10 (September 30, 2021): 985. http://dx.doi.org/10.3390/biology10100985.
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Inflammation plays a critical role in thyroid cancer onset and progression. We previously characterized the in vitro interplay between macrophages and senescent human thyrocytes and thyroid tumor-derived cell lines, modeling the early and the late thyroid tumor phases, respectively. We reported that both models are able to induce pro-tumoral M2-like macrophage polarization, through the activation of the COX2-PGE2 axis. Here, we investigated the presence of macrophage infiltrating cells in mouse xenografts derived from the above described cells models. We showed that subcutaneous injection in immunodeficient mice of both senescent human thyrocytes and thyroid tumor-derived cell lines elicits macrophage recruitment. Furthermore, considering the type of macrophage infiltrate, we observed a stronger infiltration of Arginase I positive cells (M2-like). Overall, these results demonstrate the in vivo capability of senescent and tumor thyroid cells to recruit and polarize macrophages, suggesting that the promotion of a pro-tumoral microenvironment through tumor associated macrophages may occurs in late as well as in early thyroid tumor stages, favoring tumor onset and progression.
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Warmink, Kelly, Michiel Siebelt, Philip S. Low, Frank M. Riemers, Bingbing Wang, Saskia G. M. Plomp, Marianna A. Tryfonidou, P. René van Weeren, Harrie Weinans, and Nicoline M. Korthagen. "Folate Receptor Expression by Human Monocyte–Derived Macrophage Subtypes and Effects of Corticosteroids." CARTILAGE 13, no. 1 (January 2022): 194760352210814. http://dx.doi.org/10.1177/19476035221081469.
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Objective Folate receptor beta (FR-β) has been used as a clinical marker and target in multiple inflammatory diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). However, the conditions under which FR-β+ macrophages arise remain unclear and could be affected by corticosteroids. Therefore, we studied FR-β expression in vitro in macrophage subtypes and determined their response to triamcinolone acetonide (TA), a clinically often-used corticosteroid. Design Human monocyte–derived macrophages were differentiated to the known M0, M1, or M2 macrophage phenotypes. The phenotype and FR-β expression and plasticity of the macrophage subtypes were determined using flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). Results FR-β expression was low in granulocyte-macrophage colony-stimulating factor (GM-CSF)-generated (M1-like) macrophages and high in macrophage colony-stimulating factor (M-CSF)-generated (M0 and M2-like) macrophages. FR-β expression remained high once the M0 or M2 macrophages were stimulated with pro-inflammatory stimuli (interferon-γ plus lipopolysaccharide) to induce M1-like macrophages. On the contrary, anti-inflammatory TA treatment skewed GM-CSF macrophage differentiation toward an M2 and FR-β+ phenotype. Conclusions As corticosteroids skewed monocytes toward an FR-β-expressing, anti-inflammatory phenotype, even in an M1 priming GM-CSF environment, FR-β has potential as a biomarker to monitor success of treatment with corticosteroids. Without corticosteroid treatment, M-CSF alone induces high FR-β expression which remains high under pro-inflammatory conditions. This explains why pro-inflammatory FR-β+ macrophages (exposed to M-CSF) are observed in arthritis patients and correlate with disease severity.
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Hult, Elissa M., Stephen J. Gurczynski, and Bethany B. Moore. "M2 macrophages have unique transcriptomes but conditioned media does not promote profibrotic responses in lung fibroblasts or alveolar epithelial cells in vitro." American Journal of Physiology-Lung Cellular and Molecular Physiology 321, no. 3 (September 1, 2021): L518—L532. http://dx.doi.org/10.1152/ajplung.00107.2021.
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Macrophages are critical regulators of pulmonary fibrosis. Their plasticity, proximity, and ability to cross talk with structural cells of the lung make them a key cell type of interest in the regulation of lung fibrosis. Macrophages can express a variety of phenotypes, which have been historically represented through an “M1-like” to “M2-like” delineation. In this classification, M1-like macrophages are proinflammatory and have increased phagocytic capacity compared with alternatively activated M2-like macrophages that are profibrotic and are associated with wound healing. Extensive evidence in the field in both patients and animal models aligns pulmonary fibrosis with M2 macrophages. In this study, we performed RNA sequencing (RNAseq) to fully characterize M1- vs. M2-skewed bone marrow-derived macrophages (BMDMs) and investigated the profibrotic abilities of M2 BMDM conditioned media (CM) to promote fibroblast migration and proliferation, alveolar epithelial cell (AEC) apoptosis, and mRNA expression of key fibrotic genes in both fibroblasts and AECs. Although M2 CM-treated fibroblasts had increased migration and M2 CM-treated fibroblasts and AECs had increased expression of profibrotic proteins over M1 CM-treated cells, all differences can be attributed to M2 polarization reagents IL-4 and IL-13 also present in the CM. Collectively, these data suggest that the profibrotic effects associated with M2 macrophage CM in vitro are attributable to effects of polarization cytokines rather than additional factors secreted in response to those polarizing cytokines.
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Rabani, Razieh, Allen Volchuk, Mirjana Jerkic, Lindsay Ormesher, Linda Garces-Ramirez, Johnathan Canton, Claire Masterson, et al. "Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis." European Respiratory Journal 51, no. 4 (March 8, 2018): 1702021. http://dx.doi.org/10.1183/13993003.02021-2017.
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Human mesenchymal stem/stromal cells (MSCs) have been reported to produce an M2-like, alternatively activated phenotype in macrophages. In addition, MSCs mediate effective bacterial clearance in pre-clinical sepsis models. Thus, MSCs have a paradoxical antimicrobial and anti-inflammatory response that is not understood.Here, we studied the phenotypic and functional response of monocyte-derived human macrophages to MSC exposure in vitro.MSCs induced two distinct, coexistent phenotypes: M2-like macrophages (generally elongated morphology, CD163+, acute phagosomal acidification, low NOX2 expression and limited phagosomal superoxide production) and M1-like macrophages characterised by high levels of phagosomal superoxide production. Enhanced phagosomal reactive oxygen species production was also observed in alveolar macrophages from a rodent model of pneumonia-induced sepsis. The production of M1-like macrophages was dependent on prostaglandin E2 and phosphatidylinositol 3-kinase. MSCs enhanced human macrophage phagocytosis of unopsonised bacteria and enhanced bacterial killing compared with untreated macrophages. Bacterial killing was significantly reduced by blockade of NOX2 using diphenyleneiodonium, suggesting that M1-like cells are primarily responsible for this effect. MSCs also enhanced phagocytosis and polarisation of M1-like macrophages derived from patients with severe sepsis.The enhanced antimicrobial capacity (M1-like) and inflammation resolving phenotype (M2-like) may account for the paradoxical effect of these cells in sepsis in vivo.
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Liu, Peng, Yahui Liu, Lanying Chen, Zeping Fan, Yingying Luo, and Yaru Cui. "Anemoside A3 Inhibits Macrophage M2-Like Polarization to Prevent Triple-Negative Breast Cancer Metastasis." Molecules 28, no. 4 (February 7, 2023): 1611. http://dx.doi.org/10.3390/molecules28041611.
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Triple negative breast cancer (TNBC) exhibits the characteristics of strong metastatic ability and a high recurrence rate, and M2-type macrophages play an important role in this process. Previous research data suggested that Anemoside A3 (A3), a monomeric component of Pulsatilla Chinensis, could prevent and treat TNBC by converting M0 macrophages into M1 immunogen phenotypes. This study showed that A3 significantly restrained the lung metastases of 4 T1-Luc cells with bioluminescence imaging in vivo and Hematoxylin and Eosin (H&E) staining. Meanwhile, the percentage of M2-type macrophages (CD206+ labeled cells) in the lung tissues was evidently decreased through immunohistochemical assay. We further proved that A3 markedly prevented M2-type polarization induced by IL-4 in vitro, as illustrated by the down-regulated expression of the cell surface marker CD206 protein by FACS and Arg-1, and of the Fizz1 and Ym1 genes by RT-PCR in M2-type macrophages. Furthermore, the invasion and migration of 4 T1 cells, which was promoted by the conditioned medium from M2-type macrophages, could be suppressed by A3. Luminex assay demonstrated that A3 treatment resulted in a reduction of the levels of CCL2, VEGF, CCL7, and MMP-9 in conditioned medium. Additionally, the expression of phosphorylated-STAT3 protein was inhibited by A3, which resulted in the macrophage M2-type polarization arrest, while no significant difference in JAK2 phosphorylation was detected. SiRNA transfection experiments suggested that STAT3 might be the target of A3 inhibiting M2-type polarization of macrophages. In conclusion, these results indicate that A3 could attenuate the metastasis of TNBC by inhibiting the M2-type polarization of macrophages, which may be related to the STAT3 pathway.
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Kallemeijn, Wouter W., Sarah Spear, Josephine Walton, Claudio Bussi, Christelle Soudy, Helen R. Flynn, Mark Skehel, et al. "Abstract 439: From foe to friend: In vivo reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase activity." Cancer Research 83, no. 7_Supplement (April 4, 2023): 439. http://dx.doi.org/10.1158/1538-7445.am2023-439.
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Abstract Tumor-associated macrophages (TAMs) play a central role in cancer by driving tumor growth, metastasis, therapy failure and cancer recurrence. Macrophage plasticity and diversity allows classification along a M1-M2 polarization axis, where TAMs have a M2-like polarization, associated with a pro-tumoral phenotype, whereas M1 macrophages exhibit anti-tumor functions. Reprogramming TAMs to a M1-like anti-cancer phenotype is an increasingly coveted therapeutic strategy in oncology. Here, we report TAMs can be favorably reprogrammed by modulating N-myristoyltransferase (NMT) activity using on-target, drug-like inhibitors (NMTi). We identified >100 N-myristoylated proteins differentially expressed by macrophages along the M1-M2 polarization axis. In TAM-like M2 macrophages, 42 N-myristoylated proteins exhibited higher NMTi sensitivity as compared to other polarizations, and these NMT substrates significantly enriched in anti-inflammatory, immunity- and metabolism-related pathways. Unique to TAM-like M2 macrophages, NMT modulation by NMTi induces significant transcriptomic and proteomic changes, effectively switching the polarization towards a M1-like anti-cancer phenotype that is characterized by a M1-like spindle morphology, a M1-like glycolytic state, and induction of a pro-inflammatory secretome exhibiting potent anti-tumoral activity towards ovarian cancer spheroids in vitro. In vivo proof-of-principle was established in the syngeneic, macrophage-driven ID8 mouse model for human ovarian cancer, where NMTi treatment significantly reprogrammed murine M2-like TAMs into a M1-like anti-cancer phenotype, concomitantly reducing tumor burden without observable side-effects, and significantly extending median survival by 16 days. We are currently further investigating the intricacies that N-myristoylation plays in macrophage polarization, as well as further establishing the scope of NMTi-driven in vivo reprogramming of TAMs beyond ovarian cancer. Citation Format: Wouter W. Kallemeijn, Sarah Spear, Josephine Walton, Claudio Bussi, Christelle Soudy, Helen R. Flynn, Mark Skehel, David Carling, Roberto Solari, Iain A. McNeish, Edward W. Tate. From foe to friend: In vivo reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 439.
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Horuluoglu, Begum Han, Defne Bayik, Neslihan Kayraklioglu, Emilie Goguet, Luz P. Blanco, Mariana J. Kaplan, and Dennis M. Klinman. "PAM3 supports the generation of M2-like macrophages from lupus patient monocytes and improves disease outcome in murine lupus." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 182.21. http://dx.doi.org/10.4049/jimmunol.202.supp.182.21.
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Abstract Systematic Lupus Erythematosus (SLE) is an autoimmune syndrome of unclear etiology. While T and B cell abnormalities contribute to disease pathogenesis, recent work suggests that inflammatory M1-like macrophages also play a role. Previous work showed that the TLR2/1 agonist PAM3CSK4 (PAM3) could stimulate normal human monocytes to preferentially differentiate into immunosuppressive M2-like rather than inflammatory M1-like macrophages. This raised the possibility of PAM3 being used to normalize the M1:M2 ratio in SLE. Consistent with that possibility, monocytes from lupus patients differentiated into M2-like macrophages when treated with PAM3 in vitro. Furthermore, lupus-prone NZB x NZW F1 mice responded similarly to weekly PAM3 treatment. Normalization of the M2 macrophage frequency was associated with delayed disease progression, decreased autoantibody and inflammatory cytokine synthesis, reduced proteinuria and prolonged survival in NZB x NZW F1 mice. The ability of PAM3 to bias monocyte differentiation in favor of immunosuppressive macrophages may represent a novel approach to the therapy of SLE.
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Zhang, Cong, Sisi Wei, Suli Dai, Xiaoya Li, Huixia Wang, Hongtao Zhang, Guogui Sun, Baoen Shan, and Lianmei Zhao. "The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development." Journal for ImmunoTherapy of Cancer 11, no. 5 (May 2023): e006230. http://dx.doi.org/10.1136/jitc-2022-006230.
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BackgroundTumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated.MethodsMicroarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109.ResultsWe found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activatedc-Myctranscription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163+TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer.ConclusionsOur work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer.
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Niu, Xiao-Ling, Dan Feng, Sheng Hao, Xin-Yu Kuang, Ying Wu, Guang-Hua Zhu, and Wen-Yan Huang. "The significance of M1/M2 macrophage-like monocytes in children with systemic lupus erythematosus." European Journal of Inflammation 17 (January 2019): 205873921882446. http://dx.doi.org/10.1177/2058739218824463.
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Monocytes/macrophages are important in the development of systemic lupus erythematosus. To research M1 and M2 macrophage-like monocytes in the peripheral blood of children with systemic lupus erythematosus and explore the clinical significance, M1 and M2 macrophage-like monocytes, tumor necrosis factor-α, interleukin-1, interleukin-6, interleukin-10, and interleukin-18 are tested in the peripheral blood of children with systemic lupus erythematosus by flow cytometry. A correlation analysis is made between M1 and M2 macrophage-like monocytes and erythrocyte sedimentation rate and C-reactive protein. As we found, the absolute number and percentage of M1 macrophage-like monocytes (CD163–CD14+) in macrophage-like monocytes (CD14+) in peripheral blood of the severe systemic lupus erythematosus group were higher than those of the control group and the mild–moderate systemic lupus erythematosus group ( F = 28.4, 21.7, 122, 81.7; P < 0.05). But there was no obvious difference between these three groups in terms of the absolute number of M2 macrophage-like monocytes (CD163+CD14+). The absolute number and percentage of M1 macrophage-like monocytes in macrophage-like monocytes had positive correlation with C-reactive protein and erythrocyte sedimentation rate ( r = 0.46, 0.44, 0.367, 0.47; P < 0.05); whereas, the absolute number and percentage of M2 macrophage-like monocytes in macrophage-like monocytes had negative correlation with CRP and erythrocyte sedimentation rate ( r = –0.47, –0.45, –0.47, –0.32; P < 0.05). Thus, M1 macrophage-like monocytes have effective impact on inflammation in children with systemic lupus erythematosus. M2 macrophage-like monocytes, to a large extent, have the opposite functions compared to M1 macrophage-like monocytes. In children with systemic lupus erythematosus, macrophages play important role in the development of systemic lupus erythematosus and M1 macrophage-like monocytes have functions in active systemic lupus erythematosus and they can induce the inflammation and have correlation with severity of systemic lupus erythematosus.
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Yun, Kun, Reona Sakemura, Truc Huynh, Claudia Manriquez Roman, Olivia Sirpilla, Carli Stewart, James Girsch, et al. "Abstract 6813: Immunosuppressive monocytes suppress CART19 functions through modulation of the IL-1 pathway." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6813. http://dx.doi.org/10.1158/1538-7445.am2024-6813.
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Abstract CD19-directed chimeric antigen receptor T (CART19) cell therapy has shown remarkable outcomes in B cell malignancies and was FDA approved in multiple indications, but durable remissions are limited to ~40%. Inhibitory myeloid cells in the tumor microenvironment have been found to suppress T cell expansion and contribute to CART19 failure. Here, we studied interactions between monocytes, CART19, and tumor cells to understand the impact of monocytes on CART19 effector functions. First, CD28-costimulated CART19 (CART19-28ζ) generated in the lab from healthy donors were cocultured with JeKo-1, a CD19+ mantle cell lymphoma cell line, and freshly isolated monocytes or ex vivo differentiated M2-like macrophages. M2-like macrophages were generated by incubating fresh monocytes with rhGM-CSF followed by coculturing with JeKo-1. CART19 antigen-specific proliferation was significantly inhibited by M2-like macrophages but not fresh monocytes (JeKo-1+CART19 vs JeKo-1+M2+CART19, p=0.00503). Transwell assays indicated that suppression from M2-like macrophages was not contact-dependent. IL-1 receptor antagonist (IL-1ra) was significantly elevated in M2-like macrophage coculture supernatant (JeKo-1+Mono+CART19 vs JeKo-1+M2+CART19, p=0.0292) and intracellularly in M2-like macrophages after coculture (90%+). We therefore hypothesized that M2-like macrophages inhibit CART19 by secreting IL-1ra, which blocks IL-1 signaling in CART19. We interrogated the role of IL-1ra in CART19. JeKo-1 was cocultured with CART19, supplemented with rhIL-1β only, IL-1β + IL-1ra, or IL-1β +IL-1ra + IL-1ra neutralizing antibody (neuAb). CART19 antigen-specific proliferation was improved by IL-1β (PBS vs IL-1β, p<0.0001). IL-1ra inhibited IL-1β-dependent CART19 proliferation (IL-1β vs IL-1β+IL1ra p=0.0006), which was restored by IL-1ra neutralization (IL-1β+IL-1ra vs IL-1β+IL-1ra+IL-1ra neuAb, p=0.0215). Additionally, expression of IL-1RI, the receptor of IL-1β and IL-1ra, was measured on T cells after coculturing CART19, JeKo-1, and M2-like macrophages. M2-like macrophages downregulated IL-1RI expression on CART cells, which is a potential mechanism of blocking CART response to IL-1β, resulting in further suppression of CART proliferation (JeKo-1+M2+CART19 vs JeKo-1+CART19, p=0.001). Next, we assessed the impact of IL-1ra on CART cell functions in the presence of M2-like macrophage in a mantle cell lymphoma xenograft model. NOD-SCID-γ−/- (NSG) mice were subcutaneously injected with human macrophages and luciferase+ JeKo-1 cells. Upon tumor engraftment by bioluminescent imaging, mice were randomized to treatment with CART19 + IL-1ra neuAb or control IgG for 3 weeks. CART19 + IL-1ra neuAb led to improved antitumor activity (IL-1ra neuAb vs control IgG, p=0.0033). Overall, our study revealed a role of IL-1ra in macrophage-induced CART inhibition mediated by blocking IL-1β signaling through IL-1RI. Citation Format: Kun Yun, Reona Sakemura, Truc Huynh, Claudia Manriquez Roman, Olivia Sirpilla, Carli Stewart, James Girsch, Ekene Ogbodo, Ismail Can, Jennifer Feigin, Long Mai, Hong Xia, Brooke Kimball, Makena Rodriguez, Lionel Kankeu Fonkoua, Mehrdad Hefazi, Michael Ruff, Elizabeth Siegler, Saad Kenderian. Immunosuppressive monocytes suppress CART19 functions through modulation of the IL-1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6813.
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Lu, Yufei, Leiming Guo, and Gaofeng Ding. "PD1+ tumor associated macrophages predict poor prognosis of locally advanced esophageal squamous cell carcinoma." Future Oncology 15, no. 35 (December 2019): 4019–30. http://dx.doi.org/10.2217/fon-2019-0519.
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Aim: Tumor associated macrophages are the most abundant cancer immune cells. However, little was known about the identity of CD68+PD1+ macrophages as well as the contributions in the prognosis of esophageal squamous cell carcinoma (ESCC). Methods & methods: Immunofluorescence, flowcytometry and RT-PCR were used to analysis PD1+ macrophages in ESCC. Results: CD68+PD1+ macrophages which can express higher M2 markers in cancer tissues, increased about 4.2-times compared with para-cancer tissues. Additionally, PD1high macrophages were significantly correlated with more malignant phenotypes and poor prognosis. PD1 treatment can enhance phagocytosis of cultured macrophages and redirect this macrophage to M1-like phenotype. Conclusion: Thus, our findings overall indicate that CD68+PD1+ macrophages are tumor associated macrophagess in ESCC, which can forecast the prognosis of ESCC.
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Lu, Chih-Hao, Chao-Yang Lai, Da-Wei Yeh, Yi-Ling Liu, Yu-Wen Su, Li-Chung Hsu, Chung-Hsing Chang, S. L. Catherine Jin, and Tsung-Hsien Chuang. "Involvement of M1 Macrophage Polarization in Endosomal Toll-Like Receptors Activated Psoriatic Inflammation." Mediators of Inflammation 2018 (December 16, 2018): 1–14. http://dx.doi.org/10.1155/2018/3523642.
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Psoriasis is a chronic inflammatory skin disorder that affects ~2%–3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7–9) at the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7–9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7–9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7–9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7–9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.
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Teo, Kristeen Ye Wen, Shipin Zhang, Jia Tong Loh, Ruenn Chai Lai, Hwee Weng Dennis Hey, Kong-Peng Lam, Sai Kiang Lim, and Wei Seong Toh. "Mesenchymal Stromal Cell Exosomes Mediate M2-like Macrophage Polarization through CD73/Ecto-5′-Nucleotidase Activity." Pharmaceutics 15, no. 5 (May 13, 2023): 1489. http://dx.doi.org/10.3390/pharmaceutics15051489.
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Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.
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Chae, Wook-Jin, Eun-Ah Sung, Brian Hur, and Min Hee Park. "The Wnt antagonist Dickkopf1(DKK1) promotes pulmonary fibrosis via M2-like macrophage polarization." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 13.01. http://dx.doi.org/10.4049/jimmunol.206.supp.13.01.
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Abstract Tissue fibrosis is a progressive pathological process induced by repeated tissue injury and inflammation resulting in excessive collagen deposition. The Wnt signaling pathway regulates cell proliferation and differentiation for tissue repair processes. Dickkopf1 (DKK1) is a quintessential inhibitory ligand of the Wnt pathway. M2-like macrophages, induced by type 2 cytokines such as IL-13, play a central role in tissue fibrosis. We found that DKK1 protein expression markedly increased in both lung tissues of human idiopathic pulmonary fibrosis (IPF) and lungs from the murine bleomycin (BLM)-induced fibrosis model. To investigate the role of DKK1 in lung fibrosis, we used the DKK1 hypomorphic doubleridge (Dkk1d/d) mouse model. Collagen mRNA and protein expressions were markedly decreased in the lungs of Dkk1d/d mice compared to those of WT mice upon BLM challenge. The infiltration of macrophages was significantly decreased in the lungs of Dkk1d/d mice upon lung injury. We tested whether DKK1 modulates the polarization of M2-like macrophages in vitro using mouse bone marrow-derived macrophages (BMDMs). Interestingly, DKK1 induced M2-like macrophage marker CD206 (mannose receptor) and Arginase 1 (Arg1) protein expression. The expression of CD206 and Arg1 was synergistically increased by DKK1 and IL-13. We demonstrated that DKK1 utilizes STAT6 and JNK to induce Arg1 and CD206. Taken together, our study demonstrates that DKK1 promotes pulmonary fibrosis by activation of M2-like macrophages. Our study will provide new mechanistic insights into DKK1-mediated lung fibrosis pathogenesis.
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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, Feng, Yongsheng Yang, Xiaohua Zhu, Lan Huang, and Jinhua Xu. "Macrophage Polarization Modulates Development of Systemic Lupus Erythematosus." Cellular Physiology and Biochemistry 37, no. 4 (2015): 1279–88. http://dx.doi.org/10.1159/000430251.
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Background/Aims: Macrophages have recently been shown to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the underlying mechanisms remain unclear. Methods: Here, we used an activated lymphocyte-derived DNA (ALD-DNA) method to induce SLE in mice. We used a macrophage-specific eliminator clodronate to selectively deplete macrophages in mice. We isolated macrophages from bone marrow of the mice and used cytokines to differentiate M1 and M2 macrophages, respectively. Adoptive transplantation of M1 or M2 macrophages was performed in clodronate-treated mice. The effects on SLE were evaluated by serum anti-dsDNA autoantibody, by renal pathological changes, and by urine protein levels. Results: ALD-DNA induced SLE-like features in mice, manifested by induction of serum anti-dsDNA autoantibody, by renal pathological changes, and by increases in urine protein levels. Clodronate significantly decreased macrophages in mice, which significantly increased SLE severity. Adoptive transplantation of M2, but not M1 macrophages significantly reduced SLE severity in clodronate- and ALD-DNA-treated mice. Conclusion: M1 and M2 macrophages play different roles in development of SLE. M1 macrophages increase the severity of SLE, while M2 macrophages reduce it. Modulation of macrophage polarity may be an attractive therapy for SLE.
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Mohr, Annika, Manuela Besser, Sonja Broichhausen, Maximiliane Winter, Alexander D. Bungert, Benjamin Strücker, Mazen A. Juratli, Andreas Pascher, and Felix Becker. "The Influence of Apremilast-Induced Macrophage Polarization on Intestinal Wound Healing." Journal of Clinical Medicine 12, no. 10 (May 9, 2023): 3359. http://dx.doi.org/10.3390/jcm12103359.
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There is compelling evidence suggesting a pivotal role played by macrophages in orchestrating intestinal wound healing. Since macrophages display significant plasticity and heterogeneity, exhibiting an either classically activated (M1-like) or alternatively activated (M2-like) phenotype, they can aggravate or attenuate intestinal wound healing. Growing evidence also demonstrates a causal link between impaired mucosal healing in inflammatory bowel disease (IBD) and defects in the polarization of pro-resolving macrophages. By targeting the switch from M1 to M2 macrophages, the phosphodiesterase-4 inhibitor Apremilast has gained recent attention as a potential IBD drug. However, there is a gap in our current knowledge regarding the impact of Apremilast-induced macrophages’ polarization on intestinal wound healing. The THP-1 cells were differentiated and polarized into M1 and M2 macrophages, and subsequently treated with Apremilast. Gene expression analysis was performed to characterize macrophage M1 and M2 phenotypes, and to identify possible target genes of Apremilast and the involved pathways. Next, intestinal fibroblast (CCD-18) and epithelial (CaCo-2) cell lines were scratch-wounded and exposed to a conditioned medium of Apremilast-treated macrophages. Apremilast had a clear effect on macrophage polarization, inducing an M1 to M2 phenotype switch, which was associated with NF-κB signaling. In addition, the wound-healing assays revealed an indirect influence of Apremilast on fibroblast migration. Our results support the hypothesis of Apremilast acting through the NF-κB-pathway and provide new insights into the interaction with fibroblast during intestinal wound healing.
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Ni, Ping, Yue-Qin Liu, Jin-Yu Man, Wang Li, Shan-Shan Xue, Tao-Hong Lu, Zhao-Liang Su, and Cheng-Lin Zhou. "C16, a novel sinomenine derivatives, promoted macrophage reprogramming toward M2-like phenotype and protected mice from endotoxemia." International Journal of Immunopathology and Pharmacology 35 (January 2021): 205873842110267. http://dx.doi.org/10.1177/20587384211026786.
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Macrophage plays a critical part in host defense, tissue repair, and anti-inflammation; Macrophage reprogramming is responsible for disease development or regression. We aimed to clarify the effect of sinomenine-4-hydroxy-palmitate (C16), on macrophage reprogramming and anti-inflammatory in endotoxemia model. According to a structure modification of SIN (Sinomenine), C16 was found. Then, based on the endotoxin model, the mice liver and kidney toxicity was evaluated and serum cytokines level of IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor-α), and IL-1β (Interleukin-1β) were measured by ELISA (Enzyme linked immunosorbent assay). Then, we confirmed the effect of C16 on macrophages reprogramming, we used the flow cytometry to test the effect of C16 on macrophages apoptosis in vitro. Then, iNOS (Inducible nitric oxide synthase), M1-type related cytokines, such as IL-1β, TNF-α, and M2-type related cytokines, such as Arg-1 (Arginase-1), CD206, Fizz1, and Ym1 was detected, which expressed in ANA-1 and primary peritoneal macrophages. To further explore the molecular mechanism of C16 in reprogramming of macrophages from M1 toward M2 phenotype, the expression of STAT1 (signal transducer and activator of Transcription 1), STAT3, ERK1/2 (extracellular signal regulated kinase1/2), AKT, p38, and its corresponding phosphorylation were determined by western blot. Our results demonstrated that C16 improved the survival rate of LPS- (lipopolysaccharide) challenged mice and decreased the inflammatory cytokines expression; After C16 treatment, the expression of M1 phenotype correlation factors decreased significantly, while the expression of M2 phenotype correlation factors increased significantly at different levels compared with normal group. It indicated that C16 reprogram macrophages phenotype from M1 toward M2 following LPS stimulus. Furthermore, the results also showed that C16 showed anti-inflammatory effect by inhibiting LPS-induced p38, AKT and STAT1 phosphorylation and contributing ERK1/2 activation. C16 promoted macrophage reprogramming toward M2-like phenotype via p-p38/p-AKT or STAT1 signals pathway and C16 might be a valid candidate for inflammatory disease.
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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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Rajput, Charu, Megan P. Walsh, Breanna N. Eder, Ediri E. Metitiri, Antonia P. Popova, and Marc B. Hershenson. "Rhinovirus infection induces distinct transcriptome profiles in polarized human macrophages." Physiological Genomics 50, no. 5 (May 1, 2018): 299–312. http://dx.doi.org/10.1152/physiolgenomics.00122.2017.
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Infections with rhinovirus (RV) cause asthma exacerbations. Recent studies suggest that macrophages play a role in asthmatic airway inflammation and the innate immune response to RV infection. Macrophages exhibit phenotypes based on surface markers and gene expression. We hypothesized that macrophage polarization state alters gene expression in response to RV infection. Cells were derived from human peripheral blood derived monocytes. M1 and M2 polarization was carried out by using IFN-γ and IL-4, respectively, and RNA was extracted for Affymetrix Human Gene ST2.1 exon arrays. Selected genes were validated by quantitative (q)PCR. Treatment of nonactivated (M0) macrophages with IFN-γ and IL-4 induced the expression of 252 and 153 distinct genes, respectively, including previously-identified M1 and M2 markers. RV infection of M0 macrophages induced upregulation of 232 genes; pathway analysis showed significant overrepresentation of genes involved in IFN-α/β signaling and cytokine signaling in the immune system. RV infection induced differential expression of 195 distinct genes in M1-like macrophages but only seven distinct genes in M2-like-polarized cells. In a secondary analysis, comparison between M0-, RV-infected, and M1-like-polarized, RV-infected macrophages revealed differential expression of 227 genes including those associated with asthma and its exacerbation. qPCR demonstrated increased expression of CCL8, CXCL10, TNFSF10, TNFSF18, IL6, NOD2, and GSDMD and reduced expression of VNN1, AGO1, and AGO2. Together, these data show that, in contrast to M2-like-polarized macrophages, gene expression of M1-like macrophages is highly regulated by RV.
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Meiliana, Anna, and Andi Wijaya. "Macrophage Polarization in Metabolism and Metabolic Disease." Indonesian Biomedical Journal 5, no. 2 (August 1, 2013): 81. http://dx.doi.org/10.18585/inabj.v5i2.56.
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BACKGROUND: Obesity is now recognized as the main cause of the worldwide epidemic of type 2 diabetes. Obesity-associated chronic inflammation is a contributing key factor for type 2 diabetes and cardiovascular disease. Numbers of studies have clearly demonstrated that the immune system and metabolism are highly integrated.CONTENT: Macrophages are an essential component of innate immunity and play a central role in inflammation and host defense. Moreover, these cells have homeostatic functions beyond defense, including tissue remodeling in ontogenesis and orchestration of metabolic functions. Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to interferons (IFNs), toll-like receptor (TLR), or interleukin (IL)-4/IL-13 signals, macrophages undergo M1 (classical) or M2 (alternative) activation. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1, M2 or M2-like polarized activation.SUMMARY: In response to various signals, macrophages may undergo classical M1 activation (stimulated by TLR ligands and IFN-γ) or alternative M2 activation (stimulated by IL-4/IL-13); these states mirror the T helper (Th)1–Th2 polarization of T cells. Pathology is frequently associated with dynamic changes in macrophage activation, with classically activated M1 cells implicate in initiating and sustaining inflammation, meanwhile M2 or M2-like activated cells associated with resolution or smoldering chronic inflammation. Identification of the mechanisms and molecules that are associated with macrophage plasticity and polarized activation provides a basis for macrophage centered diagnostic and therapeutic strategies.KEYWORDS: obesity, adipose tissue, inflammation, macrophage polarization
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Loureiro, J. Pedro, Mariana S. Cruz, Ana P. Cardoso, Maria J. Oliveira, and M. Fátima Macedo. "Human iNKT Cells Modulate Macrophage Survival and Phenotype." Biomedicines 10, no. 7 (July 17, 2022): 1723. http://dx.doi.org/10.3390/biomedicines10071723.
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CD1d-restricted invariant Natural Killer T (iNKT) cells are unconventional innate-like T cells whose functions highly depend on the interactions they establish with other immune cells. Although extensive studies have been reported on the communication between iNKT cells and macrophages in mice, less data is available regarding the relevance of this crosstalk in humans. Here, we dove into the human macrophage-iNKT cell axis by exploring how iNKT cells impact the survival and polarization of pro-inflammatory M1-like and anti-inflammatory M2-like monocyte-derived macrophages. By performing in vitro iNKT cell-macrophage co-cultures followed by flow cytometry analysis, we demonstrated that antigen-stimulated iNKT cells induce a generalized activated state on all macrophage subsets, leading to upregulation of CD40 and CD86 expression. CD40L blocking with a specific monoclonal antibody prior to co-cultures abrogated CD40 and CD86 upregulation, thus indicating that iNKT cells required CD40-CD40L co-stimulation to trigger macrophage activation. In addition, activated iNKT cells were cytotoxic towards macrophages in a CD1d-dependent manner, killing M1-like macrophages more efficiently than their naïve M0 or anti-inflammatory M2-like counterparts. Hence, this work highlighted the role of human iNKT cells as modulators of macrophage survival and phenotype, untangling key features of the human macrophage-iNKT cell axis and opening perspectives for future therapeutic modulation.
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Courtney, Amy N., Gengwen Tian, Daofeng Liu, Ekaterina Marinova, Andras Heczey, Xin Xu, Linjie Guo, Xiuhua Gao, and Leonid S. Metelitsa. "Cross-talk between NKT cells and tumor associated macrophages in the tumor microenvironment." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 142.7. http://dx.doi.org/10.4049/jimmunol.196.supp.142.7.
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Abstract CD1d-reactive Va24-invariant NKT cells (NKTs) control tumor growth via yet poorly understood interactions with tumor-associated macrophages (TAMs) and other myeloid cells. TAMs comprise M1- and M2-like subsets, but only CD163high M2-like TAMs are associated with poor outcome in neuroblastoma (NB) and other tumors. Here, we demonstrate that NKTs selectively target M2-like TAMs via contact-dependent and independent mechanisms. Upon direct contact with antigen-pulsed M1 or M2 macrophages, NKTs selectively killed the latter. Although the killing was strictly CD1d-dependent, CD1d expression between macrophage subsets was equivalent. In contrast, only M2-polarized macrophages expressed CD204, a scavenger receptor responsible for cellular uptake of CD1d ligands. Anti-CD204 blocking mAb inhibited NKT-cell cytotoxicity against M2 in vitro while lentiviral transduction with CD204 cDNA rendered M1 sensitive to NKT cytotoxicity. We also found that antigen-activated NKTs could reprogram M2- into functional M1-like macrophages via GM-CSF production. Furthermore, adoptive transfer of human NKTs resulted in a M1-like polarization of TAMs in metastatic NB xenografts in humanized NSG mice. However, tumors progressed even after NKT cell treatment, suggesting a tumor escape mechanism. Indeed, we found that exposure to activated NKTs resulted in rapid up-regulation of PD-L1 on both M2 and M1 subsets, which correlated with suppressed NKT proliferation and cytokine production. Thus, our results reveal a novel mechanism of immune regulation, in which NKTs control tumor-supportive inflammation via killing or reprogramming of M2-like TAMs. However NKT function is negatively regulated by TAMs at least in part in a PD-1-dependent manner.
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Myers, Kayla V., Kenneth J. Pienta, and Sarah R. Amend. "Cancer Cells and M2 Macrophages: Cooperative Invasive Ecosystem Engineers." Cancer Control 27, no. 1 (January 1, 2020): 107327482091105. http://dx.doi.org/10.1177/1073274820911058.
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Many aspects of cancer can be explained utilizing well-defined ecological principles. Applying these principles to cancer, cancer cells are an invasive species to a healthy organ ecosystem. In their capacity as ecosystem engineers, cancer cells release cytokines that recruit monocytes to the tumor and polarize them to M2-like protumor macrophages. Macrophages, recruited by the cancer cells, act as a secondary invasive species. The ecosystem engineering functions of M2-macrophages in turn support and stimulate cancer cell survival and proliferation. The cooperative ecosystem engineering of both the primary invasive species of the cancer cell and the secondary invasive species of the M2-macrophage thus creates a vicious cycle of tumor promotion. Targeting a specific aspect of this tumor-promoting ecosystem engineering, such as blocking efferocytosis by M2-like macrophages, may improve the response to standard-of-care anticancer therapies. This strategy has the potential to redirect cooperative protumor ecosystem engineering toward an antitumor ecosystem engineering strategy.
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Cornice, Jessica, Daniela Verzella, Paola Arboretto, Davide Vecchiotti, Daria Capece, Francesca Zazzeroni, and Guido Franzoso. "NF-κB: Governing Macrophages in Cancer." Genes 15, no. 2 (January 31, 2024): 197. http://dx.doi.org/10.3390/genes15020197.
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Tumor-associated macrophages (TAMs) are the major component of the tumor microenvironment (TME), where they sustain tumor progression and or-tumor immunity. Due to their plasticity, macrophages can exhibit anti- or pro-tumor functions through the expression of different gene sets leading to distinct macrophage phenotypes: M1-like or pro-inflammatory and M2-like or anti-inflammatory. NF-κB transcription factors are central regulators of TAMs in cancers, where they often drive macrophage polarization toward an M2-like phenotype. Therefore, the NF-κB pathway is an attractive therapeutic target for cancer immunotherapy in a wide range of human tumors. Hence, targeting NF-κB pathway in the myeloid compartment is a potential clinical strategy to overcome microenvironment-induced immunosuppression and increase anti-tumor immunity. In this review, we discuss the role of NF-κB as a key driver of macrophage functions in tumors as well as the principal strategies to overcome tumor immunosuppression by targeting the NF-κB pathway.
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Han, Ik-Hwan, Chanmi Jeong, Juwon Yang, Seung-Hyeok Park, Deok-Sang Hwang, and Hyunsu Bae. "Therapeutic Effect of Melittin–dKLA Targeting Tumor-Associated Macrophages in Melanoma." International Journal of Molecular Sciences 23, no. 6 (March 13, 2022): 3094. http://dx.doi.org/10.3390/ijms23063094.
Full textAbstract:
Melanoma is an immunogenic tumor and a serious type of skin cancer. Tumor-associated macrophages (TAMs) express an M2-like phenotype and are involved in all stages of melanomagenesis; it is hence a promising target for cancer immunotherapy. We herein investigated whether melittin–dKLA inhibits the growth of melanoma by inducing apoptosis of M2-like macrophages. For the in vitro study, a conditioned medium of macrophages was prepared from M0, M1, or M2-differentiated THP-1 cells with and without melittin–dKLA. The affinity of melittin for M2 macrophages was studied with FITC (fluorescein isothiocyanate)-conjugated melittin. For the in vivo study, murine melanoma cells were inoculated subcutaneously in the right flank of mice, melittin–dKLA was intraperitoneally injected at 200 nmol/kg every three days, and flow cytometry analysis of TAMs was performed. Since melittin binds preferentially to M2-like macrophages, melittin–dKLA induced more caspase 3 expression and cell death in M2 macrophages compared with M0 and M1 macrophages and melanoma cells. Melittin–dKLA significantly inhibited the proliferation and migration of M2 macrophages, resulting in a decrease in melanoma tumor growth in vivo. The CD206+ M2-like TAMs were reduced, while the CD86+ M1-like TAMs were not affected. Melittin–dKLA is therapeutically effective against melanoma by inducing the apoptosis of M2-like TAMs.
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Minopoli, Michele, Sabrina Sarno, Lucia Cannella, Salvatore Tafuto, Gosuè Scognamiglio, Michele Gallo, Flavio Fazioli, et al. "Crosstalk between Macrophages and Myxoid Liposarcoma Cells Increases Spreading and Invasiveness of Tumor Cells." Cancers 13, no. 13 (June 30, 2021): 3298. http://dx.doi.org/10.3390/cancers13133298.
Full textAbstract:
Myxoid liposarcoma (MLPS) is the second most common subtype of liposarcoma and has tendency to metastasize to soft tissues. To date, the mechanisms of invasion and metastasis of MLPS remain unclear, and new therapeutic strategies that improve patients’ outcomes are expected. In this study, we analyzed by immunohistochemistry the immune cellular components and microvessel density in tumor tissues from patients affected by MLPS. In order to evaluate the effects of primary human MLPS cells on macrophage polarization and, in turn, the ability of macrophages to influence invasiveness of MLPS cells, non-contact and 3D organotypic co-cultures were set up. High grade MLPS tissues were found heavily vascularized, exhibited a CD3, CD4, and CD8 positive T lymphocyte-poor phenotype and were massively infiltrated by CD163 positive M2-like macrophages. Conversely, low grade MLPS tissues were infiltrated by a discrete amount of CD3, CD4, and CD8 positive T lymphocytes and a scarce amount of CD163 positive macrophages. Kaplan–Meier analysis revealed a shorter Progression Free Survival in MLPS patients whose tumor tissues were highly vascularized and heavily infiltrated by CD163 positive macrophages, indicating a clear-cut link between M2-like macrophage abundance and poor prognosis in patients. Moreover, we documented that, in co-culture, soluble factors produced by primary human MLPS cells induce macrophage polarization toward an M2-like phenotype which, in turn, increases MLPS cell capability to spread into extracellular matrix and to cross endothelial monolayers. The identification of M2-like polarization factors secreted by MLPS cells may allow to develop novel targeted therapies counteracting MLPS progression.