Spatial organization of pulmonary type 2 inflammation by a macrophage-derived cholesterol metabolite

Abstract

Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear. Here, we identify a cholesterol-derived chemotactic axis that spatially organizes T helper 2 (TH2) cells during fungal-induced pulmonary type 2 inflammation. Inflammation-expanded macrophages expressing cholesterol-25-hydroxylase (CH25H) produce 25-hydroxycholesterol, which is converted into the oxysterol 7,25-dihydroxycholesterol to attract GPR183-expressing TH2 cells into infectious lesions. This TH2 positioning suppresses interferon-{gamma} responsiveness in inflammatory Ly6C macrophages, promoting fungal persistence. Disruption of this axis via TH2-specific GPR183 deletion restores type 1 macrophage activation and enhances fungal clearance. Our findings reveal a macrophage-driven, metabolite-based mechanism of immunosuppressive cell positioning in inflamed lung tissue.