Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via Kdm5b-associated epigenetic remodeling in alveolar macrophages.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present a substantial clinical burden, magnified by conditions such as COVID-19. While these conditions provide a model for exploring complex inflammatory processes, the environmental factors coordinating these responses remain poorly understood. Here, we employ comprehensive multi-omics and biochemical analyses and identify neutrophil-derived itaconate as an extracellular factor associated with sequential immune cell infiltration, including neutrophils, T cells, and monocytes. Mechanistically, extracellular itaconate metabolically facilitates Kdm5b-associated epigenetic changes at the Il6, Ccl5, and Cxcl10 gene promoters in alveolar macrophages, which are important for immune cell recruitment. Consistent with this, Mrp8-Cre Acod1fl/fl mice lacking neutrophil-derived itaconate are significantly protected from ALI-induced inflammation, with similar patterns observed in an Acinetobacter baumannii infection model. Collectively, these findings identify neutrophil-derived itaconate as an environmental factor that epigenetically shapes tiered inflammatory responses in the lung.