The mannose receptor (MR), a C-type lectin expressed on macrophages, dendritic cells and endothelial cells, can be shed from the cellular membrane and released as a soluble form in the extracellular space (sMR).

In this project, we monitored increased sMR concentrations in the serum of obese mice and humans and identified a direct correlation between sMR concentrations and metabolic markers such as body weight, blood insulin concentrations, body fat and inflammatory cytokines. Importantly, we demonstrated that circulating sMR binds and inactivates CD45 on the surface of macrophages, inducing Src/Akt signaling and activation of NFkB, which in turn results in macrophage reprogramming into a pro-inflammatory phenotype and drives the onset of metaflammation. Concomitantly, MR-deficient mice were largely protected from metaflammation-induced obesity and showed a significant reduction in inflammatory macrophages, fat accumulation and liver steatosis upon high fat diet. In contrast, direct injection with sMR even under control diet resulted in increased serum concentrations of the inflammatory cytokines TNF, IL6 and IL1b, an increase of inflammatory macrophages in fat tissue, impairments in whole body metabolism and weight gain, identifying sMR as important driver of metaflammation.

We now intend to investigate the molecular mechanisms underlying sMR shedding and its regulation by excessive caloric intake, chronic inflammation, fasting, and physical exercise. We will additionally monitor MR expression and sMR shedding in the brain, investigate whether sMR concentrations in the brain control stress vulnerability and analyze a putative effect of the sMR on lipid metabolism in adipocytes. Finally, we will search for molecules inhibiting sMR binding to CD45 on the surface of macrophages. We will test whether suchmolecules prevent pro-inflammatory macrophage activation and hence might dampen sMR-driven metaflammation, exploring the therapeutic potential of our findings.

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