IRGM Deficiency Exacerbates Sepsis-Induced Acute Lung Injury by Inhibiting Autophagy Through the AKT/mTOR Signaling Pathway
Year: 2024
Type: article
Abstract: Background: Sepsis is a life-threatening condition characterized by organ dysfunction due to an impaired immune response to infection. The lungs are highly susceptible to infection, often resulting in acute lung injury (ALI). The immune-related GTPase M (IRGM) and its murine homolog Irgm1 mediate autophagy and are implicated in inflammatory diseases, yet their roles in sepsis-induced ALI remain unclear. Methods: We used RNA sequencing and bioinformatics to explore IRGM regulation. Sepsis-induced ALI was modeled in mice using cecal ligation and puncture (CLP). An in vitro model was created by stimulating A549 cells with lipopolysaccharide (LPS). Results: In A549 cells, LPS treatment induced upregulation of IRGM expression and enhanced autophagy levels. IRGM knockdown exacerbated LPS-induced ALI, characterized by suppressed autophagy and increased apoptosis, along with significantly elevated levels of p-AKT and p-mTOR. Further investigation revealed that treatment with the AKT inhibitor MK2206 effectively reversed the autophagy inhibition caused by IRGM knockdown and reduced apoptosis. These findings suggest that the AKT/mTOR signaling pathway plays a crucial role in IRGM-mediated protection against sepsis-related ALI. Conclusion: This study identifies the protective role of IRGM in sepsis-induced ALI and reveals that IRGM mitigates ALI by promoting autophagy through inhibition of the AKT/mTOR pathway. These findings provide insights into the pathogenesis of sepsis-related ALI and highlight IRGM as a potential therapeutic target.
Source: Journal of Inflammation Research
DOI: 10.2147/jir.s496687
Authors: Na Guo, Yu Xia, Nannan He, Huixin Cheng, Lei Zhang, Jian Liu
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,836
OpenAlex ID: W4405012744