Neutrophil-derived exosomal S100A8 aggravates lung injury in sepsis by inducing pyroptosis.

Acute lung injury (ALI) is a common and life-threatening complication in patients with sepsis, with pro-inflammatory cell pyroptosis playing a crucial role in the associated organ damage. In this study, we aimed to identify potential therapeutic targets. Utilizing the GEO database (GSE232753), we analyzed the differentially expressed genes in the peripheral blood of healthy individuals and sepsis patients, identifying the significantly upregulated gene S100A8. Subsequently, we constructed a septic ALI model using lipopolysaccharide (LPS). Notably, S100A8 was highly expressed not only in serum and bronchoalveolar lavage fluid (BALF) but also in neutrophil exosomes. We then co-incubated BEAS-2B cells with neutrophil exosomes that were either treated or untreated with LPS. Cell proliferation activity was assessed using the CCK-8 assay, cell death was evaluated through propidium iodide (PI) staining, and the changes in pyroptosis indicators were detected via Western blot and ELISA. To further validate that LPS-induced neutrophil exosomes promote BEAS-2B cell pyroptosis through the delivery of S100A8, we conducted additional experiments involving the addition of S100A8 protein alone or S100A8 antibody in conjunction with neutrophil exosome treatment, followed by relevant assessments. Moreover, in vivo validation was also performed. Mechanistically, we revealed that S100A8 induces pyroptosis in BEAS-2B cells through the TLR4 signaling pathway. In conclusion, our findings provide new promising targets for the treatment of septic ALI.