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The Oxysterol Receptor GPR183 Senses Metabolic Niche Signals that Promote Differentiation of Monocytes into Tissue-Resident Lung Macrophages

ABSTRACT: Monocytes populate tissues when local niches are depleted of tissue-resident macrophages, yet the tissue-derived signals controlling monocyte-to-macrophage differentiation are largely undefined. Here, we discovered that the oxysterol receptor GPR183 enables monocytes to sense metabolic niche signals that induce lung macrophage differentiation. We found that interstitial macrophages that continuously turn over express the oxysterol receptor GPR183, whereas alveolar macrophages that derive from embryonic progenitors and slowly turn over did not. Models of conditional tissue-resident macrophage depletion showed that newcomer monocyte-derived macrophages expressed GPR183 along their differentiation trajectory. Recruited GPR183+ monocytes interacted with fibroblasts and lack of GPR183 caused defective lung macrophage differentiation. Single-cell RNA analysis over time identified lung fibroblasts as the source of the GPR183 ligand 7a,25-dihydroxycholesterol in the empty niche. Our findings identify oxysterols as key instructive signals for tissue-resident macrophage development from monocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE303395 | GEO | 2026/02/05

REPOSITORIES: GEO

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The Oxysterol Receptor GPR183 Senses Metabolic Niche Signals that Promote Differentiation of Monocytes into Tissue-Resident Lung Macrophages

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