Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation

Abstract

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.

The Mannose Receptor: From Endocytic Receptor and Biomarker to Regulator of (Meta)Inflammation

“…In accordance with other inflammatory diseases discussed above, we recently reported that serum sMR levels were increased in high-fat diet (HFD)-fed obese mice and obese humans, and positively correlated with adiposity (77). Given that the sMR induces a pro-inflammatory phenotype in macrophages as described above and proinflammatory macrophages drive insulin resistance in metabolic tissues, these observations suggested the possibility that sMR-mediated proinflammatory macrophage activation in obesity may contribute to metabolic dysfunctions.…”

“…Importantly, a recent study demonstrated that the sMR can actually drive proinflammatory macrophage activation ( 77 ). sMR induced an inflammatory phenotype of both murine and human macrophages, as reflected by increased secretion of proinflammatory cytokines (TNF, IL–6, IL–12 and IL–1β) and a shift in cellular metabolism towards increased glycolysis ( 77 ), a hallmark of proinflammatory macrophage activation ( 78 ).…”

“…Importantly, a recent study demonstrated that the sMR can actually drive proinflammatory macrophage activation ( 77 ). sMR induced an inflammatory phenotype of both murine and human macrophages, as reflected by increased secretion of proinflammatory cytokines (TNF, IL–6, IL–12 and IL–1β) and a shift in cellular metabolism towards increased glycolysis ( 77 ), a hallmark of proinflammatory macrophage activation ( 78 ). In addition, RNAseq analyses also supported macrophage reprogramming towards an inflammatory phenotype ( 77 ), as the transcriptomic signature of sMR-treated macrophages displayed close similarities with the one of macrophages treated with TNF, prostaglandin E2 and the TLR2 ligand Pam3CSK4, a combination of stimuli used in a previous study to mimic a macrophage phenotype associated with chronic inflammation ( 79 ).…”

“…At a mechanistic level, and similar to the effect of membrane-bound MR on T cells, sMR binds CD45 on macrophages, leading to an inhibition of CD45 phosphatase activity ( 77 ). Using specific inhibitors and siRNA-mediated downregulation of CD45, it was confirmed that sMR-induced proinflammatory macrophage activation was dependent on inhibition of CD45 ( Figure 4 ).…”

“…Activated Src was shown to phosphorylate Akt ( 81 ), and both phosphorylated Src and Akt were reported to promote NF-κB activation ( 82 – 85 ). Using a combination of pharmacological and genetic tools, it was demonstrated that sMR-mediated inhibition of CD45 indeed resulted in a Src/Akt/NF-κB-mediated cellular reprogramming toward an inflammatory phenotype ( Figure 4 ) ( 77 ).…”