IRGM Deficiency Exacerbates Sepsis-Induced Acute Lung Injury by Inhibiting Autophagy Through the AKT/mTOR Signaling Pathway

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2024 Dec 10

PMID 39654860

Authors

Na Guo

Yu Xia

Nannan He

Huixin Cheng

Lei Zhang

Jian Liu

Affiliations

Soon will be listed here.

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.

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