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

Abstract

The mannose receptor is a member of the C-type lectin (CLEC) family, which can bind and internalize a variety of endogenous and pathogen-associated ligands. Because of these properties, its role in endocytosis as well as antigen processing and presentation has been studied intensively. Recently, it became clear that the mannose receptor can directly influence the activation of various immune cells. Cell-bound mannose receptor expressed by antigen-presenting cells was indeed shown to drive activated T cells towards a tolerogenic phenotype. On the other hand, serum concentrations of a soluble form of the mannose receptor have been reported to be increased in patients suffering from a variety of inflammatory diseases and to correlate with severity of disease. Interestingly, we recently demonstrated that the soluble mannose receptor directly promotes macrophage proinflammatory activation and trigger metaflammation. In this review, we highlight the role of the mannose receptor and other CLECs in regulating the activation of immune cells and in shaping inflammatory responses.

Keywords: biomarker; immunometabolism; macrophage; mannose receptor; metaflammation; sCD206; sMR.

Figure 1

The CLEC family. Type I transmembrane CLECs typically contain multiple CTLDs at their extracellular region, whereas type II CLECs contain only one CLEC. All CLECs display individual expression patterns. Parts of the figure were created using templates from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com. CTLD, C-type lectin domain; FN type II, fibronectin type II domain; CR, cysteine-rich domain; CLEC, C-type lectin; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; DC, dendritic cell; MΦ, macrophage; FcRγ, Fc receptor gamma chain; C, C-terminus; N, N-terminus.

Figure 2

Cellular functions of the MR. The membrane-bound MR can recognize extracellular ligands, leading to their internalization. Endocytosed antigens are targeted into early endosomes, from which they are processed mainly for cross-presentation onto MHC I molecules and subsequent CD8⁺ T cell activation. Furthermore, the MR can assist other molecules in their signaling cascade, like enhanced TLR2 signaling after recognition of P. carinii. Finally, the MR can be shed by metalloproteases and released as a soluble form (sMR) in the extracellular space. MHC, major histocompatibility complex; MR, mannose receptor. Parts of the figure were created using templates from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 3

Membrane-bound MR on antigen presenting cells induces CD8⁺ T cell tolerance. Upon CD8⁺ T cell activation in the absence of the MR (left), expression of the transcriptional inhibitor Bcl-6 is induced. Bcl-6 binds to the CTLA-4 promoter and prevents its expression. During T cell activation in the presence of the MR (right), the MR on APCs interacts with CD45 on cytotoxic T cells. Such interaction prevents the upregulation of Bcl-6 and induces CTLA-4 expression and CD8⁺ T cell tolerance. APC, antigen presenting cell; MR, mannose receptor; TCR, T cell receptor. Parts of the figure were created using templates from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 4

The sMR induces proinflammatory activation of macrophages. Under homeostatic conditions (left), CD45 in macrophages dephosphorylates Src. At increased sMR concentrations (right), binding of sMR to CD45 inhibits its phosphatase activity, leading to phosphorylation and activation of Src, which in turn activates an Akt/NF-κB pathway, causing macrophage reprogramming towards an inflammatory phenotype. sMR, soluble mannose receptor. Parts of the figure were created using templates from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 5

The sMR in metaflammation. (A) Wild-type mice on HFD (left) have high serum sMR, which is associated with increased hepatic steatosis, CD11c+ KCs and CD11c+ ATMs. Together, this is associated with increased insulin resistance and glucose intolerance. MR-deficient mice on HFD (right) have no serum sMR, which is associated with protection against hepatic steatosis, lower CD11c+ KCs and ATMs. Together, this is associated with lower insulin resistance and glucose intolerance. (B) sMR i.p. injections in mice on chow diet increased serum proinflammatory cytokines, associated with increased proinflammatory macrophages in adipose tissue, both associated with mild insulin resistance. sMR i.p. injection in mice on HFD increased insulin resistance. ATMs; adipose tissue macrophages; i.p., intraperitoneal; HFD, high-fat diet; KCs, Kupffer cells; sMR, soluble mannose receptor. Parts of the figure were created using templates from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.