IL-36 activates neutrophil extracellular traps and exacerbates LPS-induced ARDS in mice.

Sepsis-induced acute respiratory distress syndrome (ARDS) is characterized by uncontrolled pulmonary inflammation and neutrophil-driven pathology. Neutrophil extracellular traps (NETs) have been implicated in ARDS progression, but the role of interleukin-36 (IL-36) in this process remains unclear. This study aimed to investigate the regulatory mechanism of IL-36 via NETs and its impact on NF-κB activation in a murine model of LPS-induced ARDS. A lipopolysaccharide (LPS)-induced ARDS model was established in C57BL/6 mice. Animals were divided into Control, ARDS, ARDS + IL-36, and ARDS + IL-36Ra groups. Pulmonary edema was assessed via wet/dry weight ratio, inflammatory cytokines were measured by ELISA, and histopathological changes were evaluated through H&E staining. NETs formation was analyzed using immunofluorescence and Western blot. NF-κB activation was detected via phosphorylation of p65. IL-36 administration exacerbated pulmonary edema, inflammatory cytokine levels (IL-10,TNF-α,MPO) and histopathological injury. Conversely, IL-36 receptor antagonist (IL-36Ra) attenuated these effects. IL-36 promoted NETs formation, as indicated by elevated citrullinated histone H3 (CitH3) and neutrophil elastase (NE) expression. NETs further enhanced IL-36-induced proinflammatory cytokine release and NF-κB activation in bronchial epithelial cells. IL-36Ra partially reversed NET-mediated NF-κB phosphorylation and inflammatory responses. IL-36 exacerbates LPS-induced ARDS by enhancing NETs formation and activating the NF-κB pathway, leading to amplified pulmonary inflammation and injury. Targeting IL-36 signaling may represent a potential therapeutic strategy to mitigate LPS-induced ARDS progression.