IRGM Inhibits the AKT/mTOR Signaling Pathway by Interacting with TRIM21 to Alleviate Sepsis-Induced Acute Lung Injury.

Abstract

Acute lung injury (ALI) is a severe complication of sepsis, and its underlying pathological mechanisms remain poorly understood. This study aims to investigate the role and mechanisms by which IRGM mediates autophagy through the regulation of the AKT/mTOR signaling pathway in sepsis-induced ALI. Initially, a sepsis-induced ALI mouse model was established using cecal ligation and puncture (CLP). Our results demonstrated that Irgm1 expression was significantly upregulated in the ALI model. Subsequently, Irgm1 was knocked down in vivo using AAV vectors, and changes in ALI symptoms were assessed. In vitro, a sepsis-induced ALI cell model was generated by stimulating A549 cells with lipopolysaccharide (LPS). The effects of IRGM overexpression on autophagy and apoptosis were evaluated, and its impact on the AKT/mTOR signaling pathway was analyzed. Furthermore, mass spectrometry and co-immunoprecipitation (COIP) experiments were conducted to explore the interaction between IRGM and TRIM21. In vivo results showed that Irgm1 knockout exacerbated CLP-induced ALI, as evidenced by a significant reduction in autophagic activity, increased apoptosis, and aberrant activation of the AKT/mTOR pathway. Further cellular experiments suggested that IRGM may enhance autophagy by inhibiting the AKT/mTOR signaling pathway, thereby attenuating LPS-induced cell damage. Additionally, COIP experiments revealed that IRGM interacts with TRIM21 to inhibit AKT/mTOR pathway activation, thereby promoting autophagy and mitigating sepsis-induced ALI. In conclusion, IRGM regulates autophagy through the AKT/mTOR signaling pathway and exerts protective effects in sepsis-induced ALI, suggesting that it may serve as a potential therapeutic target for sepsis-related ALI.