Synergistic inhibition of CitH3 and S100A8/A9: A novel therapeutic strategy for mitigating sepsis-induced inflammation and lung injury.

OBJECTIVE: Sepsis is a life-threatening condition with high global morbidity and mortality. Citrullinated histone H3 (CitH3) has gained recognition as a significant biomarker for early sepsis diagnosis and management. This study aims to investigate the therapeutic potential of targeting both CitH3 and S100A8/A9 to reduce sepsis-induced inflammation and organ damage. METHODS: Using a novel CitH3 antibody distinct from commercial options, we analyzed serum samples from LPS-treated mice through a co-immunoprecipitation assay followed by LC-MS/MS proteomic analysis to explore the interaction between CitH3 and S100A8/A9 proteins in peripheral blood. Additionally, in a Pseudomonas aeruginosa (PA)-induced lung injury model, we assessed CitH3 and S100A8/A9 levels in bronchoalveolar lavage fluid (BALF), alveolar samples, and neutrophils to determine their influence on neutrophil activation and inflammatory responses. RESULTS: Our study revealed, for the first time, that CitH3 and S100A8/A9 synergistically promoted neutrophil activation, inflammatory responses, and NETosis, which exacerbated lung injury in sepsis. Dual targeting of CitH3 and S100A8/A9 significantly reduced neutrophil recruitment, NETosis, and inflammation in the PA-induced lung injury model. This therapeutic approach improved lung injury and survival rates, accompanied by a shift in cytokine profiles, with reductions in pro-inflammatory cytokines and increases in anti-inflammatory cytokines. CONCLUSION: These findings underscore the potential of dual targeting CitH3 and S100A8/A9 as a novel therapeutic approach for sepsis. This combined intervention shows promising effects in reducing inflammation and enhancing survival, offering a groundbreaking strategy for sepsis diagnosis and treatment.