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

Zheng, Y.; Dobson, H. E.; Jean Pierre, M.; LeBlanc, L.; Onyishi, C. U.; Golec, D. P.; Carrillo, N.; Deewan, A.; Rivera, C. A.; Ansaldo, E.; Dang, E. V.

doi:10.1101/2025.07.29.666625

bioRxiv · 10.1101/2025.07.29.666625

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

Zheng, Y.·Dobson, H. E.·Jean Pierre, M.·LeBlanc, L.·Onyishi, C. U.·Golec, D. P.·Carrillo, N.·Deewan, A.·Rivera, C. A.·Ansaldo, E.·Dang, E. V.

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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.

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Zheng, Y., Dobson, H. E., Jean Pierre, M., LeBlanc, L., Onyishi, C. U., Golec, D. P., Carrillo, N., Deewan, A., Rivera, C. A., Ansaldo, E., Dang, E. V.. 2025-08-01. Spatial organization of pulmonary type 2 inflammation by a macrophage-derived cholesterol metabolite. https://doi.org/10.1101/2025.07.29.666625

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