| First Author | Vural A | Year | 2019 |
| Journal | J Immunol | Volume | 202 |
| Issue | 5 | Pages | 1510-1520 |
| PubMed ID | 30683698 | Mgi Jnum | J:272934 |
| Mgi Id | MGI:6280805 | Doi | 10.4049/jimmunol.1801145 |
| Citation | Vural A, et al. (2019) Galphai2 Signaling Regulates Inflammasome Priming and Cytokine Production by Biasing Macrophage Phenotype Determination. J Immunol 202(5):1510-1520 |
| abstractText | 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 Galpha signaling links these receptors to downstream effectors. Several Galphai-coupled G-protein-coupled receptors have been implicated in macrophage polarization. In this study, we use genetically modified mice to investigate the role of Galphai2 on inflammasome activity and macrophage polarization. We report that Galphai2 in murine bone marrow-derived macrophages (BMDMs) regulates IL-1beta release after activation of the NLRP3, AIM2, and NLRC4 inflammasomes. We show this regulation stems from the biased polarity of Galphai2 deficient (Gnai2 (-/-)) and RGS-insensitive Galphai2 (Gnai2 (G184S/G184S)) BMDMs. We determined that although Gnai2 (G184S/G184S) BMDMs (excess Galphai2 signaling) have a tendency toward classically activated proinflammatory (M1) phenotype, Gnai2(-/-) BMDMs (Galphai2 deficient) are biased toward alternatively activated anti-inflammatory (M2) phenotype. Finally, we find that Galphai2-deficient macrophages have increased Akt activation and IFN-beta production but defects in ERK1/2 and STAT3 activation after LPS stimulation. Galphai2-deficient macrophages also exhibit increased STAT6 activation after IL-4 stimulation. In summary, our data indicates that excess Galphai2 signaling promotes an M1 macrophage phenotype, whereas Galphai2 signaling deficiency promotes an M2 phenotype. Understanding Galphai2-mediated effects on macrophage polarization may bring to light insights regarding disease pathogenesis and the reprogramming of macrophages for the development of novel therapeutics. |
