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

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. Overall design: To define the cellular source of the GPR183 ligand, single-cell RNAseq was performed in lung fibroblasts, endothelial cells, and epithelial cells before and after DT-mediated alveolar macrophage depletion.

当局部组织微龛缺乏组织驻留巨噬细胞时，单核细胞会浸润组织，但调控单核细胞向巨噬细胞分化的组织源性信号仍未得到充分阐明。本研究发现，氧固醇受体GPR183（oxysterol receptor GPR183）可使单核细胞感知诱导肺巨噬细胞分化的代谢微龛信号。我们观察到，持续更新的间质巨噬细胞表达氧固醇受体GPR183，而源自胚胎祖细胞且更新缓慢的肺泡巨噬细胞则不表达该受体。通过条件性组织驻留巨噬细胞清除模型实验，我们发现新迁入的单核细胞来源巨噬细胞在其分化轨迹中均表达GPR183。募集而来的GPR183阳性单核细胞可与成纤维细胞相互作用，而GPR183缺失会导致肺巨噬细胞分化缺陷。时序性单细胞RNA测序分析鉴定出，在空置的组织微龛中，肺成纤维细胞是GPR183配体7α,25-二羟胆固醇（7a,25-dihydroxycholesterol）的来源。本研究证实，氧固醇类物质是单核细胞分化为组织驻留巨噬细胞的关键指导性信号。实验设计概述：为明确GPR183配体的细胞来源，本研究在白喉毒素（Diphtheria Toxin, DT）介导的肺泡巨噬细胞清除前后，分别对肺成纤维细胞、内皮细胞及上皮细胞开展了单细胞RNA测序。