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 and inhibits its phosphatase activity, leading to a Src/Akt/NF-κB-mediated cellular reprogramming towards an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Additionally, MR deficiency lowers pro-inflammatory macrophages in metabolic tissues and protects against hepatic steatosis and whole-body metabolic dysfunctions in high-fat diet-induced obese mice. Conversely, administration of sMR in lean mice increases serum pro-inflammatory cytokines, activates tissue macrophages and promotes insulin resistance. Altogether, our results reveal sMR as novel regulator of pro-inflammatory macrophage activation which could constitute a new therapeutic target for metaflammation and other hyperinflammatory diseases.

中文翻译：

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可溶性甘露糖受体诱导促炎性巨噬细胞活化和发炎

代谢组织中巨噬细胞的促炎性激活在诱导肥胖引起的发炎中至关重要。在这里，我们证明了可溶性甘露糖受体（sMR）在巨噬细胞激活和发炎中都起着直接的功能性作用。我们显示，sMR结合巨噬细胞上的CD45并抑制其磷酸酶活性，从而导致Src / Akt /NF-κB介导的细胞重编程在炎性表型中在体外和体内。值得注意的是，在肥胖的小鼠和人类中观察到血清sMR水平升高，并且与体重直接相关。此外，MR缺乏症可降低代谢组织中的促炎性巨噬细胞，并防止高脂饮食诱导的肥胖小鼠发生肝脂肪变性和全身代谢功能障碍。反过来，在瘦小鼠中施用sMR可增加血清促炎细胞因子，激活组织巨噬细胞并促进胰岛素抵抗。总的来说，我们的结果表明sMR是促炎性巨噬细胞激活的新型调节剂，可能构成新的治疗靶标，以治疗炎症和其他炎症性疾病。