Proinflammatory activation of macrophages in metabolic tissues is critically important in the 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 an Src/Akt/NF-κB–mediated cellular reprogramming toward 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. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.

代谢组织中巨噬细胞的促炎激活在诱导肥胖诱导的元炎症中至关重要。在这里，我们证明可溶性甘露糖受体 (sMR) 在巨噬细胞活化和元炎症中发挥直接的功能作用。我们显示 sMR 结合巨噬细胞上的 CD45 并抑制其磷酸酶活性，导致 Src/Akt/NF-κB 介导的细胞重编程在体外和体内均朝向炎症表型。值得注意的是，在肥胖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。重要的是，增强的 sMR 水平会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。总之，我们的结果揭示了 sMR 作为促炎性巨噬细胞活化的调节剂，