2. Academic Validation
  3. RGS2 is an innate immune checkpoint for suppressing Gαq-mediated IFNγ generation and lung injury

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

  • iScience. 2025 Jan 27;28(2):111878. doi: 10.1016/j.isci.2025.111878.
Jagdish Chandra Joshi 1 2,  Bhagwati Joshi 1,  Cuiping Zhang 3,  Somenath Banerjee 1,  Vigneshwaran Vellingiri 1,  Vijay Avin Balaji Raghunathrao 1,  Mumtaz Anwar 1,  Tejas Pravin Rokade 1,  Lianghui Zhang 4,  Ruhul Amin 1,  Yuanlin Song 3,  Dolly Mehta 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Centre for Lung and Vascular Biology, University of Illinois, College of Medicine, Chicago, IL, USA.
  • 2 Lake Erie College of Osteopathic Medicine, School of Pharmacy, Erie, PA, USA.
  • 3 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Vascular Medicine Institute, Center for Vaccine Research, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
PMID: 40041768 DOI: 10.1016/j.isci.2025.111878
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.

Keywords

Immunology; Molecular biology.

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