Novel Cell-to-Cell Communications Between Macrophages and Fibroblasts Regulate Obesity-Induced Adipose Tissue Fibrosis

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Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular cross talk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we used single-cell analytical approaches to investigate cell-to-cell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLS), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported lipid-associated macrophages (LAMs), we found a small subcluster expressing macrophage-inducible C-type lectin (Mincle), specifically localizing to CLS. Mincle signaling increased the expression of oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, OSM expression was positively correlated with MINCLE expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLS. ARTICLE HIGHLIGHTS: Adipose tissue fibrosis is a complex and dynamic process that involves many cell types, such as macrophages and fibroblasts. Crown-like structures, which drive inflammation and fibrosis in obesity, are excellent targets for single-cell and spatial transcriptomics. We found novel cell-to-cell communications between macrophages and fibroblasts in adipose tissue from diet-induced obese mice, particularly during the fibrotic phase. We elucidated the role of the macrophage-inducible C-type lectin-oncostatin M axis in obesity-induced adipose tissue fibrosis.

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