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

IF 6.4 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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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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g - αq/11通过促进内质网应激介导的NETosis加重小鼠急性肺损伤。

背景：急性肺损伤（ALI）的特点是中性粒细胞胞外陷阱（NETs）增加、临床死亡率升高和缺乏靶向治疗干预。Gαq/11蛋白是G蛋白亚家族的一员，是多种疾病的有效干预靶点，但对其在ALI中的作用知之甚少。方法：采用髓细胞特异性Gna11敲除小鼠，建立脂多糖（LPS）诱导的小鼠ALI模型。观察小鼠肺病理变化，采集肺标本进行免疫荧光染色和rna测序分析，探讨g - αq/11对ALI的影响及其机制。分离培养小鼠骨髓源性中性粒细胞，进行活细胞成像研究g - αq/11的体外作用。结果：ALI小鼠肺组织中g - αq/11表达上调，与炎症基因表达升高一致。髓系细胞特异性Gna11缺陷减轻lps诱导的小鼠肺损伤和NETs的形成。在机制上，Gαq/11通过促进中性粒细胞内质网（ER）应激传感器IRE1α的激活和介导线粒体活性氧（mitoROS）的产生来促进NETosis。YM-254,890对g - αq/11的药理抑制可减少NETs的形成和小鼠肺损伤。结论：g - αq/11的上调通过促进内质网应激介导的NETosis而加重ALI。因此，g - αq/11是治疗ALI的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.