RGS2 is an innate immune checkpoint for suppressing Gαq-mediated IFNγ generation and lung injury

Interferon gamma (IFNγ), a type II interferon, augments tissue inflammation following infections, leading to lethal acute lung injury (ALI), yet the mechanisms controlling IFNγ generation in the lungs remain elusive. Here, we identified regulator of G protein signaling 2 (RGS2) as a gatekeeper of the lung's IFNγ levels during infections. Deletion of RGS2 sustained an increase in IFNγ levels in macrophages, leading to unresolvable inflammatory lung injury. This response was not seen in RGS2 null chimeric mice receiving wild-type (WT) bone marrow or the RGS2 gene in alveolar macrophages (AMs) or IFNγ-blocking antibody. RGS2 functioned by suppressing Gαq-mediated IFNγ generation and AM inflammatory signaling. Thus, the inhibition of Gαq blocked IFNγ generation in AMs and rewired AM transcriptomes from an inflammatory to a reparative phenotype in RGS2 null mice, pointing to the RGS2-Gαq axis as a potential target for suppressing inflammatory injury.

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Publication Details

Journal
iScience
Published
2025-01-27
DOI
https://doi.org/10.1016/j.isci.2025.111878
Citations
8
Primary Topic
Immune Response and Inflammation
Type
article
Field-Weighted Citation Impact
6.38

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RGS2 is an innate immune checkpoint for suppressing Gαq-mediated IFNγ generation and lung injury

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iScience
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article

RGS2 is an innate immune checkpoint for suppressing Gαq-mediated IFNγ generation and lung injury

V. Vigneshwaran, Vijay Avin Balaji Raghunathrao, Yuanlin Song, Tejas Pravin Rokade, Mumtaz Anwar, Jagdish Chandra Joshi, Lianghui Zhang, Dolly Mehta, Cuiping Zhang, Md Ruhul Amin, Somenath Banerjee, Bhagwati Joshi
article en
8 citations

Abstract

Interferon gamma (IFNγ), a type II interferon, augments tissue inflammation following infections, leading to lethal acute lung injury (ALI), yet the mechanisms controlling IFNγ generation in the lungs remain elusive. Here, we identified regulator of G protein signaling 2 (RGS2) as a gatekeeper of the lung's IFNγ levels during infections. Deletion of RGS2 sustained an increase in IFNγ levels in macrophages, leading to unresolvable inflammatory lung injury. This response was not seen in RGS2 null chimeric mice receiving wild-type (WT) bone marrow or the RGS2 gene in alveolar macrophages (AMs) or IFNγ-blocking antibody. RGS2 functioned by suppressing Gαq-mediated IFNγ generation and AM inflammatory signaling. Thus, the inhibition of Gαq blocked IFNγ generation in AMs and rewired AM transcriptomes from an inflammatory to a reparative phenotype in RGS2 null mice, pointing to the RGS2-Gαq axis as a potential target for suppressing inflammatory injury.

iScienceVol. 28(2)
University of Illinois Urbana-Champaign (US), Sun Yat-sen University (CN), Illinois College (US), University of Pittsburgh (US), Lake Erie College of Osteopathic Medicine (US), Fudan University (CN), University of Illinois Chicago (US), Zhongshan Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN)
Université de Lausanne, National Institutes of Health, University of Illinois at Urbana-Champaign
Good health and well-being
Openalex Percentile: Top 3%
Immune Response and Inflammation
6.38
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