Regulation of lung macrophage differentiation and function by cholesterol metabolites

<p dir="ltr">Monocyte-derived macrophages play an important role in lung disease. Yet, the signals driving the differentiation of infiltrating monocytes to macrophages in the inflamed lung remain poorly understood. Tissue damage causes the production of inflammatory metabolites. We found that hydroxylated cholesterol metabolites called oxysterols were increased in the injured lung. In patients with chronic inflammatory lung disease, we discovered monocytes expressing the oxysterol receptor GPR183. In this thesis, I determined that monocytes required the GPR183 receptor to migrate towards oxysterols in vitro. Competitive bone marrow chimera experiments and new genetic models of specific lung macrophage depletion showed that GPR183 promotes occupation of macrophage niches after depletion by monocytes in vivo. Lung fibroblasts were identified as a likely cellular source of oxysterols through single-cell RNA sequencing analysis. Oxysterolexpressing fibroblasts and macrophages were confirmed to be in close proximity in situ. These findings demonstrate how recognition of oxysterols by GPR183 plays an important role in monocyte-to-macrophage differentiation in the injured lung. Targeting cholesterol metabolism could be a novel way to improve the outcome of lung disease.</p>