Serum mannose receptor promotes pro-inflammatory macrophage activation and obesity-associated metaflammation

Elevated serum concentrations of the soluble mannose receptor (sMR) have been reported to correlate with the severity of various inflammatory diseases. A physiological role of sMR, however, remains unclear. Here, 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-?B-mediated signaling. Remarkably, increased serum sMR levels correlate with obesity in both mice and humans. In addition, 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 induces serum pro-inflammatory cytokines and pro-inflammatory macrophages in the liver and promote insulin resistance. Altogether, our results reveal sMR as novel regulator of pro-inflammatory macrophage activation and could constitute a novel therapeutic target for hyperinflammatory diseases. Overall design: To dissect the effect of the soluble Mannose Receptor (MR) on macrophages, we treated MR-deficient macrophages with a recombinant fusion protein between the Fc region of human IgG1 and the extracellular region of the MR (FcMR) for 4 h, 12 h or 24 h and isolated mRNA for RNA-seq analysis.