RGS2 is an Innate Immune Checkpoint for Suppressing Gαq-mediated IFNγ Generation and Lung Injury

Overview

Journal iScience

Publisher Cell Press

Date 2025 Mar 5

PMID 40041768

Authors

Jagdish Chandra Joshi

Bhagwati Joshi

Cuiping Zhang

Somenath Banerjee

Vigneshwaran Vellingiri

Vijay Avin Balaji Raghunathrao

Mumtaz Anwar

Tejas Pravin Rokade

Lianghui Zhang

Ruhul Amin

Yuanlin Song

Dolly Mehta

Affiliations

Soon will be listed here.

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.

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