Sepsis-induced lung injury is a common critical condition in clinical practice, characterized by the accumulation of peroxides and inflammatory damage caused by excessive macrophage activation. Currently, effective treatments for sepsis-induced lung injury are lacking. Short-chain fatty acid receptor FFAR2 serves as an anti-inflammatory biomarker, but its role and mechanism in sepsis-induced lung injury remain unclear. To elucidate the influence and mechanism of FFAR2 on macrophage lipid peroxidation levels in sepsis-induced lung injury, this study conducted bioinformatics analysis and cellular experiments using the THP-1 macrophage cell line. By dual luciferase reporter and chromatin immunoprecipitation-quantitative PCR assays, it is confirmed that the transcription factor VDR upregulates FFAR2 expression in macrophages by binding to the promoter region -1695 ∼ 1525, thereby increasing the expression of iron death negative regulatory molecules and lowering macrophage lipid peroxidation levels. Moreover, both in vitro using THP-1 cells and bone marrow-derived macrophages (BMDMs) and in vivo using an LPS-induced septic mice model experiments revealed that activating the VDR/FFAR2 axis could reduce inflammation-induced macrophage lipid peroxide accumulation and alleviate lung injury in septic mice. This finding highlights the potential of FFAR2 as an immunotherapeutic target for mitigating sepsis-related lung injury.
Keywords: Acute lung injury; Lipid peroxidation; Macrophage; Sepsis.
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