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Macrophage Polarization Modulates Fc?R- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression.

ABSTRACT: In response to microenvironmental cues, macrophages undergo a profound phenotypic transformation acquiring distinct activation phenotypes ranging from pro-inflammatory (M1) to anti-inflammatory (M2). To study how activation phenotype influences phagocytosis and production of reactive oxygen species (ROS) mediated by receptors for IgG antibodies (Fc? receptors) and by CD13, human monocyte-derived macrophages were polarized to distinct phenotypes using IFN-? (M?-IFN-?), IL-4 (M?-IL-4), or IL-10 (M?-IL-10). Phenotypically, M?-IFN-? were characterized as CD14+CD80+CD86+ cells, M?-IL-4 as CD209highCD206+CD11b+CD14low, and M?-IL-10 as CD16+CD163+ cells. Compared to non-polarized macrophages, Fc?RI expression increased in M?-IFN-? and M?-IL-10 and Fc?RIII expression increased in M?-IL-10. None of the polarizing cytokines modified Fc?RII or CD13 expression. Functionally, we found that cytokine-mediated activation significantly and distinctively affected Fc?R- and CD13-mediated phagocytosis and ROS generation. Compared to non-polarized macrophages, Fc?RI-, Fc?RII-, and CD13-mediated phagocytosis was significantly increased in M?-IL-10 and decreased in M?-IFN-?, although both cytokines significantly upregulated Fc?RI expression. IL-10 also increased phagocytosis of Escherichia coli, showing that the effect of IL-10 on macrophage phagocytosis is not specific for a particular receptor. Interestingly, M?-IL-4, which showed poor Fc?R- and CD13-mediated phagocytosis, showed very high phagocytosis of E. coli and zymosan. Coupled with phagocytosis, macrophages produce ROS that contribute to microbial killing. As expected, M?-IFN-? showed significant production of ROS after Fc?RI-, Fc?RII-, or CD13-mediated phagocytosis. Unexpectedly, we found that M?-IL-10 can also produce ROS after simultaneous stimulation through several phagocytic receptors, as coaggregation of Fc?RI/Fc?RII/CD13 induced a belated but significant ROS production. Together, these results demonstrate that activation of macrophages by each cytokine distinctly modulates expression of phagocytic receptors, Fc?R- and CD13-mediated phagocytosis, and ROS production.

SUBMITTER: Mendoza-Coronel E

PROVIDER: S-EPMC5366847 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Macrophage Polarization Modulates FcγR- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression.

Mendoza-Coronel Elizabeth E Ortega Enrique E

Frontiers in immunology 20170327

In response to microenvironmental cues, macrophages undergo a profound phenotypic transformation acquiring distinct activation phenotypes ranging from pro-inflammatory (M1) to anti-inflammatory (M2). To study how activation phenotype influences phagocytosis and production of reactive oxygen species (ROS) mediated by receptors for IgG antibodies (Fcγ receptors) and by CD13, human monocyte-derived macrophages were polarized to distinct phenotypes using IFN-γ (Mϕ-IFN-γ), IL-4 (Mϕ-IL-4), or IL-10 (M ...[more]

PMID: 28396660

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Project description:Tumor associated macrophages (TAM) enhance the aggressiveness of breast cancer via promoting cancer cell growth, metastasis, and suppression of the patient's immune system. These TAMs are polarized in breast cancer with features more closely resembling the pro-tumorigenic and immunosuppressive M2 type rather than the anti-tumor and pro-inflammatory M1 type. The goal of our study was to examine primary human monocyte-derived M1 and M2 macrophages for key redox differences and determine sensitivities of these macrophages to the redox-active drug, MnTE-2-PyP5+. This compound reduced levels of M2 markers and inhibited their ability to promote cancer cell growth and suppress T cell activation. The surface levels of the T cell suppressing molecule, PD-L2, were reduced by MnTE-2-PyP5+ in a dose-dependent manner. This study also examined key differences in ROS generation and scavenging between M1 and M2 macrophages. Our results indicate that M2 macrophages have lower levels of reactive oxygen species (ROS) and lower production of extracellular hydrogen peroxide compared to the M1 macrophages. These differences are due in part to reduced expression levels of pro-oxidants, Nox2, Nox5, and the non-enzymatic members of the Nox complex, p22phox and p47phox, as well as higher levels of antioxidant enzymes, Cu/ZnSOD, Gpx1, and catalase. More importantly, we found that despite having lower ROS levels, M2 macrophages require ROS for proper polarization, as addition of hydrogen peroxide increased M2 markers. These TAM-like macrophages are also more sensitive to the ROS modulator and a pan-Nox inhibitor. Both MnTE-2-PyP5+ and DPI inhibited expression levels of M2 marker genes. We have further shown that this inhibition was partly mediated through a decrease in Stat3 activation during IL4-induced M2 polarization. Overall, this study reveals key redox differences between M1 and M2 primary human macrophages and that redox-active drugs can be used to inhibit the pro-tumor and immunosuppressive phenotype of TAM-like M2 macrophages. This study also provides rationale for combining MnTE-2-PyP5+ with immunotherapies.

Dataset Information

Macrophage Polarization Modulates Fc?R- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression.

Publications

Macrophage Polarization Modulates FcγR- and CD13-Mediated Phagocytosis and Reactive Oxygen Species Production, Independently of Receptor Membrane Expression.

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