IL‐37 Protects Against Ventilator‐Induced Lung Injury by Inhibiting NLRP3 Activation

ABSTRACT Mechanical ventilation is an effective strategy for managing acute respiratory distress syndrome (ARDS), but it can also exacerbate lung injury, leading to ventilator‐induced lung injury (VILI). To investigate the protective role of interleukin‐37 (IL‐37) in the pathogenesis of VILI, we used two approaches, human IL‐37 transgenic (IL37tg) mice and administration of recombinant human IL‐37 (rIL37) in wild‐type (WT) mice subjected to mechanical ventilation. Lung histopathology was evaluated, inflammatory cytokine levels (IL‐1β, IL‐6, TNF‐α) were measured, and inflammasome activation was assessed by analyzing NLRP3 and Caspase‐1 expression. As a result, IL37tg mice exhibited significantly attenuated lung injury compared to WT controls, characterized by improved histological morphology, reduced lung injury scores, and decreased infiltration of macrophages and neutrophils. Similarly, rIL37 administration markedly reduced lung injury and decreased inflammatory cytokine levels. Immunofluorescence analysis revealed colocalization of the alveolar cell marker surfactant protein D (SP‐D) and IL‐37. Furthermore, IL‐37 suppressed NLRP3 inflammasome activation, as evidenced by reduced NLRP3 and Cleaved‐Caspase‐1 levels in both the IL37tg mouse model and the rIL37 treatment group. These findings suggest that IL‐37 effectively protects against VILI by inhibiting inflammation in lung tissues through inhibition of the NLRP3 inflammasome. Therefore, IL‐37 may serve as a potential therapeutic target for the prevention and treatment of VILI in the future.