S100A9 lactylation facilitated sepsis-related acute respiratory distress syndrome via promoting transcription activation of IL-1β in macrophages

BACKGROUND: Sepsis is a severe inflammatory condition often complicated by acute lung injury (ALI) with limited therapeutic options. S100 Calcium Binding Protein A9 (S100A9) as an alarmin is highly elevated in sepsis. We observed that S100A9 was lactylated in the lung tissues of septic mice, the role of which in regulating sepsis-related ALI remains unknown. METHODS: S100A9 lactylation sites were identified in septic patients and CLP mice using immunoprecipitation and mass spectrometry. Mechanistic studies employed mutagenesis, co-immunoprecipitation, and luciferase assays. RESULTS: In this study, we confirmed that S100A9 was lactylated at K4 and K94 in septic patients. Lactylated S100A9 promoted its nuclear translocation, thereby enhancing its interaction with transcription factor CCAAT/enhancer-binding protein beta (Cebpb). The complex of S100A9 and Cebpb further promoted the transcriptional activation of downstream interleukin 1 beta (IL-1β), leading to sepsis-related ALI. Moreover, the knockout of S100A9 effectively alleviated sepsis-induced inflammatory response and lung injury. CONCLUSIONS: Our findings elucidated the importance of S100A9 lactylation in regulating inflammatory responses of macrophages in sepsis-induced ALI, providing novel insights into the pathophysiology of sepsis and potential therapeutic targets for sepsis-associated organ dysfunction.