| 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.Metaflammation defines a chronic inflammatory state in response to prolonged excessive nutrient intake and is characterized by low-grade inflammation of metabolic tissues (1). Macrophage reprogramming toward an inflammatory phenotype plays a critical role in obesity-induced metaflammation (2, 3). In lean individuals, macrophages in metabolic tissues maintain tissue homeostasis and insulin sensitivity, potentially through secreting anti-inflammatory cytokines, for example, TGF-β and IL-10 (1). In metaflammation, however, macrophages in adipose tissue and liver are activated through proinflammatory factors in their microenvironment, such as high levels of saturated free fatty acids (FA) and IFN-γ. Consequently, these macrophages produce high amounts of tumor necrosis factor (TNF), which directly inhibits canonical insulin signaling (4), leading to ectopic fat deposition in the liver and in skeletal muscles (5). Additionally, activation of Kupffer cells (KCs), the liver-resident macrophages, promotes recruitment and activation of inflammatory monocytes, which contribute to hepatic insulin resistance and steatosis (6–8).The MR (also termed CD206) is a type I transmembrane protein belonging to the C-type lectin family, which is mainly expressed by subpopulations of macrophages, dendritic cells, and endothelial cells (9, 10). The MR consists of a cysteine-rich region, a fibronectin type II domain, eight C-type lectin-like domains (CTLDs), a transmembrane region, and a short cytosolic tail. Due to its high affinity for glycosylated antigens, the MR plays an important role in antigen uptake and presentation (11, 12). In addition to its functions as a transmembrane protein, the extracellular part of the MR can be shed by metalloproteases and released into the extracellular space (13, 14). Hence, soluble MR (sMR) can be detected in murine and human serum, and its level was found to be increased in patients with a variety of inflammatory diseases (15–20), correlating with severity of disease and even mortality. However, a physiological role of the sMR has not been studied yet, and it remains unclear whether the sMR can actively trigger inflammation.Here, we report that sMR enhances macrophage proinflammatory activation, both in vitro and in vivo, and promotes metaflammation. We demonstrate that the sMR directly interacts with CD45 on the surface of macrophages and inhibits its phosphatase activity, leading to Src/Akt/NF-κB–mediated cellular reprogramming toward an inflammatory phenotype. Additionally, we found enhanced sMR serum levels in obese mice and humans and show that sMR-induced activation of macrophages triggers metaflammation in vivo. |
