Soluble mannose receptor induces pro-inflammatory macrophage activation and obesity-associated metaflammation

Pro-inflammatory activation of macrophages in metabolic tissues is critically important in induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct, functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages, both in vitro and in vivo, leading to cellular reprogramming towards an inflammatory phenotype by inhibition of CD45 phosphatase activity, which induces Src/Akt/NF-{kappa}B-mediated signaling. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Additionally, MR deficiency lowers the high-fat diet-induced increase in pro-inflammatory macrophages in metabolic tissues and protects against hepatic steatosis and whole-body metabolic dysfunctions. Conversely, administration of sMR in lean mice induces serum pro-inflammatory cytokines, activates tissue macrophages and promotes insulin resistance. Altogether, our results reveal sMR as novel regulator of pro-inflammatory macrophage activation and metaflammation, and could constitute a novel therapeutic target for hyperinflammatory diseases.