Interleukin-39 aggravates sepsis by inducing self-sustaining neutrophil activation in the lungs via the CXCL1-CXCR2 pathway.

Background: Sepsis, a life-threatening condition, involves dysregulated host responses to infection that frequently lead to multi-organ failure. Despite advancements in supportive care, current therapies for this disease remain limited, necessitating novel treatment approaches. Interleukin-39 (IL-39), a recently identified member of the IL-12 family, has emerged as a key mediator of inflammatory diseases; however, its functional role in the pathogenesis of sepsis remains largely unknown. Methods: Serum levels of IL-39 were analyzed in septic patients and healthy individuals. A cecal ligation and puncture (CLP)-induced sepsis murine model was employed. Recombinant human IL-39 (rhIL-39) or an IL-39-neutralizing antibody was administered to CLP mice to investigate both the causative role of IL-39 as well as the anti-IL-39 therapeutic potential. The survival rates, the severity of pulmonary injuries, the levels of pro-inflammatory cytokines, and the infiltration of neutrophils in septic mice were assessed. Bulk RNA sequencing was performed to explore the mechanisms underlying IL-39 promotion of sepsis. Results: Septic patients had significantly elevated serum levels of IL-39 compared to healthy individuals. The levels of IL-39 were strongly correlated with clinical severity and 90-day mortality in the septic patients. In CLP-induced septic mice, rhIL-39 administration enhanced pulmonary damage, increased systemic inflammation and worsened overall survival. Conversely, IL-39 neutralizing antibodies reversed these effects and improved the survival outcome. Mechanistically, RNA sequencing analysis revealed IL-39 treatment markedly increased several chemokines and pro-inflammatory cytokines, and enriched "cytokine-cytokine receptor interaction" pathway. Finally, rhIL-39 enhanced neutrophil recruitment to lung tissues, a process that was proven to be linked to the CXCL1-CXCR2 pathway activation by Conclusions: This study demonstrates that IL-39 is a critical exacerbating factor in sepsis progression, driving neutrophil-mediated tissue injury via CXCL1-CXCR2 signaling. These findings identify IL-39 as both a prognostic biomarker and a promising potential therapeutic target for sepsis management.