C-Type Lectin Receptors
Ontology highlight
ABSTRACT:
SUBMITTER: Kabashima K
PROVIDER: S-EPMC7121771 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
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Project description:C-type lectin receptors (CLRs) are a large family of soluble and trans-membrane pattern recognition receptors that are widely and primarily expressed on myeloid cells. CLRs are important for cell-cell communication and host defense against pathogens through the recognition of specific carbohydrate structures. Similar to a family of Toll-like receptors, CLRs signaling are involved in the various steps for initiation of innate immune responses and promote secretion of soluble factors such as cytokines and interferons. Moreover, CLRs contribute to endocytosis and antigen presentation, thereby fine-tune adaptive immune responses. In addition, there may also be a direct activation of acquired immunity. On the other hand, glycans, such as mannose structures, Lewis-type antigens, or GalNAc are components of tumor antigens and ligate CLRs, leading to immunoregulation. Therefore, agonists or antagonists of CLRs signaling are potential therapeutic reagents for cancer immunotherapy. We aim to overview the current knowledge of CLRs signaling and the application of their ligands on tumor-associating immune response.
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Project description:Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.
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Project description:Helicobacter pylori causes gastritis, which has been attributed to the development of H. pylori-specific T cells during infection. However, the mechanism underlying innate immune detection leading to the priming of T cells is not fully understood, as H. pylori evades TLR detection. Here, we report that H. pylori metabolites modified from host cholesterol exacerbate gastritis through the interaction with C-type lectin receptors. Cholesteryl acyl α-glucoside (αCAG) and cholesteryl phosphatidyl α-glucoside (αCPG) were identified as noncanonical ligands for Mincle (Clec4e) and DCAR (Clec4b1). During chronic infection, H. pylori-specific T cell responses and gastritis were ameliorated in Mincle-deficient mice, although bacterial burdens remained unchanged. Furthermore, a mutant H. pylori strain lacking αCAG and αCPG exhibited an impaired ability to cause gastritis. Thus H. pylori-specific modification of host cholesterol plays a pathophysiological role that exacerbates gastric inflammation by triggering C-type lectin receptors.
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Project description:C-type lectin receptors and their adaptor molecules are involved in the recognition of glycosylated self-antigens and pathogens. However, little is known about the species- and organ-specific expression profiles of these molecules. We therefore determined the mRNA expression levels of Dectin-1, MR1, MR2, DC-SIGN, Syk, Card-9, Bcl-10, Malt-1, Src, Dec-205, Galectin-1, Tim-3, Trem-1, and DAP-12 in 11 solid organs of human and mice. Mouse organs revealed lower mRNA levels of most molecules compared to spleen. However, Dec-205 and Galectin-1 in thymus, Src in brain, MR2, Card-9, Bcl-10, Src, and Dec-205 in small intestine, MR2, Bcl-10, Src, Galectin-1 in kidney, and Src and Galectin-1 in muscle were at least 2-fold higher expressed compared to spleen. Human lung, liver and heart expressed higher mRNA levels of most genes compared to spleen. Dectin-1, MR1, Syk and Trem-1 mRNA were strongly up-regulated upon ischemia-reperfusion injury in murine kidney. Tim3, DAP-12, Card-9, DC-SIGN and MR2 were further up-regulated during renal fibrosis. Murine kidney showed higher DAP-12, Syk, Card-9 and Dectin-1 mRNA expression during the progression of lupus nephritis. Thus, the organ-, and species-specific expression of C-type lectin receptors is different between mice and humans which must be considered in the interpretation of related studies.
| S-EPMC3431848 | biostudies-literature
Project description:Fungi, usually present as commensals, are a major cause of opportunistic infections in immunocompromised patients. Such infections, if not diagnosed or treated properly, can prove fatal. However, in most cases healthy individuals are able to avert the fungal attacks by mounting proper antifungal immune responses. Among the pattern recognition receptors (PRRs), C-type lectin receptors (CLRs) are the major players in antifungal immunity. CLRs can recognize carbohydrate ligands, such as ?-glucans and mannans, which are mainly found on fungal cell surfaces. They induce proinflammatory immune reactions, including phagocytosis, oxidative burst, cytokine, and chemokine production from innate effector cells, as well as activation of adaptive immunity via Th17 responses. CLRs such as Dectin-1, Dectin-2, Mincle, mannose receptor (MR), and DC-SIGN can recognize many disease-causing fungi and also collaborate with each other as well as other PRRs in mounting a fungi-specific immune response. Mutations in these receptors affect the host response and have been linked to a higher risk in contracting fungal infections. This review focuses on how CLRs on various immune cells orchestrate the antifungal response and on the contribution of single nucleotide polymorphisms in these receptors toward the risk of developing such infections.
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Project description:Neutrophil-mediated cytotoxicity toward tumor cells requires cell contact and is mediated by hydrogen peroxide. We have recently shown that Cathepsin G expressed on the neutrophil surface interacts with tumor RAGE, and this interaction facilitates neutrophil cytotoxicity. Interruption of the Cathepsin G-RAGE interaction led to 50-80% reduction in cytotoxicity, suggesting that additional interactions are also involved. Here we show that blocking antibodies to the C-type lectin receptors (CLRs) Clec4e and Dectin-1, but not those to NKG2D, attenuated murine neutrophil cytotoxicity towards murine tumor cells, suggesting a contributing role for these CLRs in neutrophil recognition of tumor cells. We further observed that the CLRs interact with tumor Nidogen-1 and Hspg2, two sulfated glycoproteins of the basement membrane. Both Nidogen-1 and Hspg2 were found to be expressed on the tumor cell surface. The knockdown of Nidogen-1, but not that of Hspg2, led to reduced susceptibility of the tumor cells to neutrophil cytotoxicity. Altogether, this study suggests a role for CLR-Nidogen-1 interaction in the recognition of tumor cells by neutrophils, and this interaction facilitates neutrophil-mediated killing of the tumor cells.
| S-EPMC9030733 | biostudies-literature
Project description:The group of pattern recognition receptors includes families of Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors. They are key sensors for a number of infectious agents, some of which are oncogenic, and they launch an immune response against them, normally promoting their eradication. Inherited variations in genes encoding these receptors and proteins and their signaling pathways may affect their function, possibly modulating cancer risk and features of cancer progression. There are numerous studies investigating the association of single nucleotide polymorphisms within or near genes encoding Toll-like receptors and NOD-like receptors, cancer risk, and features of cancer progression. However, there is an almost total absence of articles analyzing the correlation between polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk or progression. Nevertheless, there is some evidence supporting the hypothesis that inherited C-type lectin receptor and RIG-I-like receptor variants can be associated with increased cancer risk. Certain C-type lectin receptors and RIG-I-like receptors recognize pathogen-associated molecular patterns of potentially oncogenic infectious agents, and certain polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors may have functional consequences at the molecular level that can lead to association of such single nucleotide polymorphisms with risk or progression of some diseases that may modulate cancer risk, so these gene polymorphisms may affect cancer risk indirectly. Polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors thereby may be correlated with a risk of lung, oral, esophageal, gastric, colorectal, and liver cancer, as well as nasopharyngeal carcinoma, glioblastoma, multiple myeloma, and lymphoma. The list of the most promising polymorphisms for oncogenomic investigations may include rs1926736, rs2478577, rs2437257, rs691005, rs2287886, rs735239, rs4804803, rs16910526, rs36055726, rs11795404, and rs10813831.
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Project description:C-type lectin-like receptors (CLRs) represent a family of transmembrane pattern recognition receptors, expressed primarily by myeloid cells. They recognize not only pathogen moieties for host defense, but also modified self-antigens such as damage-associated molecular patterns released from dead cells. Upon ligation, CLR signaling leads to the production of inflammatory mediators to shape amplitude, duration and outcome of the immune response. Thus, following excessive injury, dysregulation of these receptors leads to the development of inflammatory diseases. Herein, we will focus on four CLRs of the "Dectin family," shown to decode the immunogenicity of cell death. CLEC9A on dendritic cells links F-actin exposed by dying cells to favor cross-presentation of dead-cell associated antigens to CD8+ T cells. Nevertheless, CLEC9A exerts also feedback mechanisms to temper neutrophil recruitment and prevent additional tissue damage. MINCLE expressed by macrophages binds nuclear SAP130 released by necrotic cells to potentiate pro-inflammatory responses. However, the consequent inflammation can exacerbate pathogenesis of inflammatory diseases. Moreover, in a tumor microenvironment, MINCLE induces macrophage-induced immune suppression and cancer progression. Similarly, triggering of LOX-1 by oxidized LDL, amplifies pro-inflammatory response but promotes tumor immune escape and metastasis. Finally, CLEC12A that recognizes monosodium urate crystals formed during cell death, inhibits activating signals to prevent detrimental inflammation. Interestingly, CLEC12A also sustains type-I IFN response to finely tune immune responses in case of viral-induced collateral damage. Therefore, CLRs acting in concert as sensors of injury, could be used in a targeted way to treat numerous diseases such as allergies, obesity, tumors, and autoimmunity.
| S-EPMC7040094 | biostudies-literature
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 innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.
| S-EPMC7279300 | biostudies-literature