Medicinal chemistry of the myeloid C-type lectin receptors Mincle, Langerin, and DC-SIGN.
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ABSTRACT:
SUBMITTER: Cramer J
PROVIDER: S-EPMC8672822 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:C-Type Lectin Receptors (CTLR) are involved in the activation of innate and adaptative immune responses. Among these receptors, the Dendritic Cell-Specific ICAM-3-Grabbing nonintegrin (DC-SIGN/CD209) has become a hot topic due to its ability to bind and facilitate the infections processes of several pathogens. Although well characterized in mammals, little documentation exists about the receptor in salmonid fishes. Here, we report the sequence and expression analysis of eight DC-SIGN-like genes in Salmo salar. Each receptor displays structural similarities to DC-SIGN molecules described in mammals, including internalization motifs, a neck region with heptad repeats, and a Ca+2-dependent carbohydrate recognition domain. The receptors are expressed in multiple tissues of fish, and fish cell lines, with differential expression upon infection with viral and bacterial pathogens. The identification of DC-SIGN-like receptors in Salmo salar provides new information regarding the structure of the immune system of salmon, potential markers for cell subsets, as well as insights into DC-SIGN conservation across species.
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Project description:The C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) can serve as a docking site for pathogens on the surface of dendritic cells. Pathogen binding to DC-SIGN can have diverse consequences for the host. DC-SIGN can facilitate HIV-1 dissemination, but the interaction of Mycobacterium tuberculosis with DC-SIGN is important for host immunity. The ability of pathogens to target DC-SIGN provides impetus to identify ligands that can perturb these interactions. Here, we describe the first stable small molecule inhibitors of DC-SIGN. These inhibitors were derived from a collection of quinoxalinones, which were assembled using a tandem cross metathesis-hydrogenation sequence. To assess the ability of these small molecules to block DC-SIGN-mediated glycan adhesion and internalization, we developed a sensitive flow cytometry assay. Our results reveal that the quinoxalinones are effective inhibitors of DC-SIGN-glycan interactions. These compounds block both glycan binding to cells and glycan internalization. We anticipate that these non-carbohydrate inhibitors can be used to elucidate the role of DC-SIGN in pathogenesis and immune function.
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Project description:In the immune system, C-type lectins and CTLDs have been shown to act both as adhesion and as pathogen recognition receptors. The Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and its homologs in human and mouse represent an important C-type lectin family. DC-SIGN contains a lectin domain that recognizes in a Ca2+-dependent manner carbohydrates such as mannose-containing structures present on glycoproteins such as ICAM-2 and ICAM-3. DC-SIGN is a prototype C-type lectin organized in microdomains, which have their role as pathogen recognition receptors in sensing microbes. Although the integrin LFA-1 is a counter-receptor for both ICAM-2 and ICAM-3 on DC, DC-SIGN is the high affinity adhesion receptor for ICAM-2/-3. While cell–cell contact is a primary function of selectins, collectins are specialized in recognition of pathogens. Interestingly, DC-SIGN is a cell adhesion receptor as well as a pathogen recognition receptor. As adhesion receptor, DC-SIGN mediates the contact between dendritic cells (DCs) and T lymphocytes, by binding to ICAM-3, and mediates rolling of DCs on endothelium, by interacting with ICAM-2. As pathogen receptor, DC-SIGN recognizes a variety of microorganisms, including viruses, bacteria, fungi and several parasites (Cambi et al. 2005). The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. In this chapter, we shall focus on the structure and functions of DC-SIGN and related CTLDs in the recognition of pathogens, the molecular and structural determinants that regulate the interaction with pathogen-associated molecular patterns. The heterogeneity of carbohydrate residues exposed on cellular proteins and pathogens regulates specific binding of DC-expressed C-type lectins that contribute to the diversity of immune responses created by DCs (van Kooyk et al. 2003a; Cambi et al. 2005).
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Project description:The C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is found on the surface of dendritic cells. It can mediate adhesion between dendritic cells and T lymphocytes and facilitate antigen capture and presentation. Many pathogens can exploit DC-SIGN binding for nefarious purposes. For example, DC-SIGN can facilitate the dissemination of viruses, like HIV-1. Alternatively, some microbes (e.g., Mycobacterium tuberculosis) use their ability to interact with DC-SIGN to evade immune detection. The diverse roles attributed to DC-SIGN provide impetus to identify ligands that can be used to explore its different functions. Such compounds also could serve as therapeutic leads. Most of the DC-SIGN ligands studied previously are mannose- or fucose-derived monosaccharides or oligosaccharides with inhibitory constants in the range of 0.1-10 mM. To identify monovalent ligands with more powerful DC-SIGN blocking properties, we devised a high-throughput fluorescence-based competition assay. This assay afforded potent non-carbohydrate, small molecule inhibitors (IC50 values of 1.6-10 microM). These compounds block not only DC-SIGN-carbohydrate interactions but also DC-SIGN-mediated cell adhesion. Thus, we anticipate that these non-carbohydrate inhibitors can be used to illuminate the role of DC-SIGN in pathogenesis and immune function.
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Project description:Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors' expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS.
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Project description:Multivalent binding of glycans on pathogens and on mammalian cells by the receptors DC-SIGN (CD209) and DC-SIGNR (L-SIGN, CD299) is dependent on correct disposition of the C-type carbohydrate-recognition domains projected at the C-terminal ends of necks at the cell surface. In the work reported here, neck domains of DC-SIGN and DC-SIGNR expressed in isolation are shown to form tetramers in the absence of the CRDs. Stability analysis indicates that interactions between the neck domains account fully for the stability of the tetrameric extracellular portions of the receptors. The neck domains are approximately 40% alpha-helical based on circular dichroism analysis. However, in contrast to other glycan-binding receptors in which fully helical neck regions are intimately associated with C-terminal C-type CRDs, the neck domains in DC-SIGN and DC-SIGNR act as autonomous tetramerization domains and the neck domains and CRDs are organized independently. Neck domains from polymorphic forms of DC-SIGNR that lack some of the repeat sequences show modestly reduced stability, but differences near the C-terminal end of the neck domains lead to significantly enhanced stability of DC-SIGNR tetramers compared to DC-SIGN.
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