PMID- 30683698
OWN - NLM
STAT- MEDLINE
DCOM- 20191112
LR  - 20200309
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 202
IP  - 5
DP  - 2019 Mar 1
TI  - Galpha(i2) Signaling Regulates Inflammasome Priming and Cytokine Production by 
      Biasing Macrophage Phenotype Determination.
PG  - 1510-1520
LID - 10.4049/jimmunol.1801145 [doi]
AB  - 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 Galpha(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 Galpha(i2) on inflammasome 
      activity and macrophage polarization. We report that Galpha(i2) 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 Galpha(i2) deficient (Gnai2 (-/-)) and RGS-insensitive Galpha(i2) 
      (Gnai2 (G184S/G184S)) BMDMs. We determined that although Gnai2 (G184S/G184S) 
      BMDMs (excess Galpha(i2) signaling) have a tendency toward classically activated 
      proinflammatory (M1) phenotype, Gnai2(-/-) BMDMs (Galpha(i2) deficient) are biased 
      toward alternatively activated anti-inflammatory (M2) phenotype. Finally, we find 
      that Galpha(i2)-deficient macrophages have increased Akt activation and IFN-beta 
      production but defects in ERK1/2 and STAT3 activation after LPS stimulation. 
      Galpha(i2)-deficient macrophages also exhibit increased STAT6 activation after IL-4 
      stimulation. In summary, our data indicates that excess Galpha(i2) signaling promotes 
      an M1 macrophage phenotype, whereas Galpha(i2) signaling deficiency promotes an M2 
      phenotype. Understanding Galpha(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.
CI  - Copyright (c) 2019 by The American Association of Immunologists, Inc.
FAU - Vural, Ali
AU  - Vural A
AUID- ORCID: 0000-0002-1269-6338
AD  - B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National 
      Institute of Allergy and Infectious Diseases, National Institutes of Health, 
      Bethesda, MD 20892.
FAU - Nabar, Neel R
AU  - Nabar NR
AUID- ORCID: 0000-0002-9704-3570
AD  - 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.
AD  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 
      Stockholm, Sweden; and.
FAU - Hwang, Il-Young
AU  - Hwang IY
AD  - B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National 
      Institute of Allergy and Infectious Diseases, National Institutes of Health, 
      Bethesda, MD 20892.
FAU - Sohn, Silke
AU  - Sohn S
AUID- ORCID: 0000-0002-7051-0933
AD  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 
      Stockholm, Sweden; and.
FAU - Park, Chung
AU  - Park C
AUID- ORCID: 0000-0002-7819-5333
AD  - B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National 
      Institute of Allergy and Infectious Diseases, National Institutes of Health, 
      Bethesda, MD 20892.
FAU - Karlsson, Mikael C I
AU  - Karlsson MCI
AD  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 
      Stockholm, Sweden; and.
FAU - Blumer, Joe B
AU  - Blumer JB
AUID- ORCID: 0000-0002-0020-3815
AD  - Department of Cell and Molecular Pharmacology and Experimental Therapeutics, 
      Medical University of South Carolina, Charleston, SC 29425.
FAU - Kehrl, John H
AU  - Kehrl JH
AUID- ORCID: 0000-0002-6526-159X
AD  - 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.
LA  - eng
GR  - ZIA AI000961-10/Intramural NIH HHS/United States
GR  - ZIA AI000961-11/Intramural NIH HHS/United States
GR  - ZIA AI000961-13/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190125
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Cytokines)
RN  - 0 (Inflammasomes)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunit, Gi2)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cytokines/*biosynthesis
MH  - GTP-Binding Protein alpha Subunit, Gi2/deficiency/*immunology
MH  - Inflammasomes/*immunology
MH  - Macrophages/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phenotype
MH  - Signal Transduction/*immunology
PMC - PMC6382563
MID - NIHMS1517381
EDAT- 2019/01/27 06:00
MHDA- 2019/11/13 06:00
PMCR- 2020/03/01
CRDT- 2019/01/27 06:00
PHST- 2018/08/17 00:00 [received]
PHST- 2018/12/19 00:00 [accepted]
PHST- 2019/01/27 06:00 [pubmed]
PHST- 2019/11/13 06:00 [medline]
PHST- 2019/01/27 06:00 [entrez]
PHST- 2020/03/01 00:00 [pmc-release]
AID - jimmunol.1801145 [pii]
AID - 10.4049/jimmunol.1801145 [doi]
PST - ppublish
SO  - J Immunol. 2019 Mar 1;202(5):1510-1520. doi: 10.4049/jimmunol.1801145. Epub 2019 
      Jan 25.