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i2 Signaling Regulates Inflammasome Priming and Cytokine Production by Biasing Macrophage Phenotype Determination.
Vural, Ali; Nabar, Neel R; Hwang, Il-Young; Sohn, Silke; Park, Chung; Karlsson, Mikael C I; Blumer, Joe B; Kehrl, John H.
Afiliação
  • Vural A; B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • Nabar NR; B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; neel.nabar@nih.gov jkehrl@niaid.nih.gov.
  • Hwang IY; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
  • Sohn S; B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • Park C; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
  • Karlsson MCI; B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • Blumer JB; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
  • Kehrl JH; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425.
J Immunol ; 202(5): 1510-1520, 2019 03 01.
Article em En | MEDLINE | ID: mdl-30683698
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 Gα signaling links these receptors to downstream effectors. Several Gαi-coupled G-protein-coupled receptors have been implicated in macrophage polarization. In this study, we use genetically modified mice to investigate the role of Gαi2 on inflammasome activity and macrophage polarization. We report that Gαi2 in murine bone marrow-derived macrophages (BMDMs) regulates IL-1ß release after activation of the NLRP3, AIM2, and NLRC4 inflammasomes. We show this regulation stems from the biased polarity of Gαi2 deficient (Gnai2 -/-) and RGS-insensitive Gαi2 (Gnai2 G184S/G184S) BMDMs. We determined that although Gnai2 G184S/G184S BMDMs (excess Gαi2 signaling) have a tendency toward classically activated proinflammatory (M1) phenotype, Gnai2-/- BMDMs (Gαi2 deficient) are biased toward alternatively activated anti-inflammatory (M2) phenotype. Finally, we find that Gαi2-deficient macrophages have increased Akt activation and IFN-ß production but defects in ERK1/2 and STAT3 activation after LPS stimulation. Gαi2-deficient macrophages also exhibit increased STAT6 activation after IL-4 stimulation. In summary, our data indicates that excess Gαi2 signaling promotes an M1 macrophage phenotype, whereas Gαi2 signaling deficiency promotes an M2 phenotype. Understanding Gαi2-mediated effects on macrophage polarization may bring to light insights regarding disease pathogenesis and the reprogramming of macrophages for the development of novel therapeutics.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Citocinas / Subunidade alfa Gi2 de Proteína de Ligação ao GTP / Inflamassomos / Macrófagos Limite: Animals Idioma: En Revista: J Immunol Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Citocinas / Subunidade alfa Gi2 de Proteína de Ligação ao GTP / Inflamassomos / Macrófagos Limite: Animals Idioma: En Revista: J Immunol Ano de publicação: 2019 Tipo de documento: Article