期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 5, 页码 1510-1520出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801145
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资金
- intramural program of the National Institutes of Allergy and Infectious Diseases
- Thomas Jefferson University M.D., Ph.D. training program
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000739] Funding Source: NIH RePORTER
Macrophages exist as innate immune subsets that exhibit phenotypic heterogeneity and functional plasticity. Their phenotypes are dictated by inputs from the tissue microenvironment. G-protein-coupled receptors are essential in transducing signals from the microenvironment, and heterotrimeric G alpha signaling links these receptors to downstream effectors. Several G alpha(i)-coupled G-protein-coupled receptors have been implicated in macrophage polarization. In this study, we use genetically modified mice to investigate the role of G alpha(i2) on inflammasome activity and macrophage polarization. We report that G alpha(i2) in murine bone marrow-derived macrophages (BMDMs) regulates IL1 beta release after activation of the NLRP3, AIM2, and NLRC4 inflammasomes. We show this regulation stems from the biased polarity of G alpha(i2) deficient (Gnai2(-/-)) and RGS-insensitive G alpha(i2) (Gnai2(G184S/G184S)) BMDMs. We determined that although Gnai2(G184S/G184S) BMDMs (excess G alpha(i2) signaling) have a tendency toward classically activated proinflammatory (M1) phenotype, Gnai2(-/-) BMDMs (G alpha(i2) deficient) are biased toward alternatively activated anti-inflammatory (M2) phenotype. Finally, we find that G alpha(i2)-deficient macrophages have increased Akt activation and IFN-beta production but defects in ERK1/2 and STAT3 activation after LPS stimulation. G alpha(i2)-deficient macrophages also exhibit increased STAT6 activation after IL-4 stimulation. In summary, our data indicates that excess G alpha(i2) signaling promotes an M1 macrophage phenotype, whereas G alpha(i2) signaling deficiency promotes an M2 phenotype. Understanding G alpha(i2)-mediated effects on macrophage polarization may bring to light insights regarding disease pathogenesis and the reprogramming of macrophages for the development of novel therapeutics.
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