Gαq/11 aggravates acute lung injury in mice by promoting endoplasmic reticulum stress-mediated NETosis.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Medicine Pub Date : 2025-02-19 DOI:10.1186/s10020-025-01118-4

Qian Xiang, Yang Tian, Kai Yang, Yaqin Du, Jian Xie

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引用次数: 0

Abstract

Background: Acute lung injury (ALI) is distinguished by exaggerated neutrophil extracellular traps (NETs), elevated clinical mortality rates, and a paucity of targeted therapeutic interventions. The Gαq/11 protein, a member of the G protein subfamily, is an effective intervention target for a variety of diseases, but little is known about its role in ALI.

Methods: In this study, a murine model of ALI induced by lipopolysaccharide (LPS) was utilized, employing myeloid cell-specific Gna11 knockout mice. The pulmonary pathology of mice was assessed and the lung samples were collected for immunofluorescence staining and RNA-sequencing analysis to elucidate the impact and underlying mechanisms of Gαq/11 in ALI. Mouse bone marrow-derived neutrophils were isolated and cultured for live-cell imaging to investigate the in vitro effects of Gαq/11.

Results: The expression of Gαq/11 was found to be upregulated in the lung tissues of mice with ALI, coinciding with the increased expression of inflammatory genes. Myeloid cell-specific Gna11 deficience attenuated LPS-induced lung injury and the formation of NETs in mice. Mechanistically, Gαq/11 facilitates NETosis by promoting the activation of the endoplasmic reticulum (ER) stress sensor IRE1α in neutrophils and mediating the production of mitochondrial reactive oxygen species (mitoROS). Pharmacological inhibition of Gαq/11 using YM-254,890 was shown to reduce NETs formation and lung injury in mice.

Conclusions: The upregulation of Gαq/11 exacerbates ALI through the promotion of ER stress-mediated NETosis. Consequently, Gαq/11 represents a potential therapeutic target for the treatment of ALI.

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.