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C-Type Lectin Receptors
C-type lectin receptors (CLRs) comprise a large family of receptors that bind to carbohydrates in a calcium-dependent manner. The lectin activity of these receptors is mediated by conserved carbohydrate-recognition domains (CRDs). CLRs include dectin-1, the dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), DC-SIGN related (DC-SIGNR) and the circulating mannose binding lectin (MBL). These CLRs share one or more CRD that were originally found in the mannose-binding lectin and are evolutionarily conserved. These receptors have been shown to be involved in fungal recognition and the modulation of the innate immune response. CLRs are expressed by most cell types including macrophages and dendritic cells (DCs), which internalize various glycoproteins and microbes for the purposes of clearance and antigen presentation to T lymphocytes.
Dectin-1 is a recently discovered pattern-recognition receptor that plays an important role in antifungal innate immunity. Dectin-1, which is expressed on phagocytes, is a specific receptor for β-glucans [1]. β-Glucans are glucose polymers found in the cell walls of fungi, including the yeasts Saccharomyces cerevisiae and Candida albicans. Dectin-1 binds and internalizes β-glucans and mediates the production of reactive oxygen species (ROS), activation of NF-κB and subsequent secretion of proinflammatory cytokines. Zymosan, a cell wall preparation of S. cerevisiae composed primarily of β-glucan, mannan, mannoprotein and chitin, induces immune responses that are both Dectin-1 and TLR2-dependent [2]. However, it is now clear that its β-glucan moiety triggers NF-κB activation only through Dectin-1 as treatment with hot alkali or organic solvents abrogates the TLR2-dependent response [2,3]. Dectin-1 is a type II transmembrane protein with a CRD connected by a stalk to the transmembrane region, followed by a cytoplasmic tail containing an immunoreceptor tyrosinase-based activation motif (ITAM). Dectin-1 binds specifically to β-1,3 glucans and induces its own signaling pathway [4,5]. After binding to its ligand, Dectin-1 is phosphorylated by a non-receptor tyrosinase kinase Src. Syk is then activated and induces the CARD9-Bcl10-Malt1 complex. This complex mediates the activation of NF-κB and the production of proinflammatory cytokines. Recent data suggest that Dectin-1 and TLR2/TLR6 signalings combine to enhance the responses triggered by each receptor [2,5].
Human DC-SIGN is of special interest because it is involved in the interaction of certain DCs with several viruses (HIV-1, HCV, dengue virus, CMV, ebola virus) and other microbes, Leishmania and Candida species. This type II transmembrance protein has a single C-type lectin domain and is expressed on immature monocyte-derived DCs. Five mouse DC-SIGN homologues exist. Only one of these named mDC-SIGN is expressed in a restricted fashion in DCs, while the others have a different tissue distribution and are termed SIGNR1, SIGNR2, SIGNR3 and SIGNR4 for SIGN-related proteins [6].
Despite similarities in the carbohydrate recognition domains (CRDs) of the mouse homologues to the hDC-SIGN, the membrane proximal neck domains were much shorter.
A molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-κB has been identified. It has been demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-κB subunit p65, but only after TLR-induced activation of NF-κB. Acetylation of p65 both prolonged and increased IL-10 transcription to enhance anti-inflammatory cytokine response.
It has been demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and HIV-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs7. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.
MBL, a soluble C-type lectin, is an effector molecule of the innate immune system. MBL plays a crucial role in innate immunity against yeast by enhanced complement activation and enhanced uptake of polymorphonuclear cells [8]. MBL binds to repetitive mannose and/or N-acetylglucosamine residues on microorganisms, leading to opsonization and activation of the lectin complement pathway. MBL also interacts with carbohydrates on the glycoprotein (gp)120 of HIV-1. MBL may inhibit DC-SIGN-mediated uptake and spread of HIV[9]. Differences exist in polysaccharide recognition, endocytic capacities and microbe capture among CLRs. Furthermore, the ligands and
physiological functions of many of the CLRs are still unknown. Mincle is one such orphan receptor. Mincle is the first example of a CLR that recognizes an endogenous nuclear ligand and necrotic cells [10].
1.Brown GD. et al. , 2003. Dectin-1 mediates the biological effects of beta glucans. J Exp Med. 197: 1119- 24.
2. Gantner BN. et al., 2003. Collaborative induction of inflammatory responses by dectin-1 and Toll- like receptor 2. J Exp Med. 197: 1107-17.
3. Ikeda Y. et al., 2008. Dissociation of Toll- like receptor 2-mediated innate immune response to Zymosan by organic solvent treatment without loss of Dectin-1 reactivity.Biol Pharm Bull. 31(1): 13- 8.
4. Gross O. et al., 2006. Card9 controls a non-TLR signaling pathway for innate anti-fungal immunity. Nature. 442:651- 6.
5. Dennehy KM. & Brown GD., 2007. The role of the beta-glucan receptor Dectin-1 in control of fungal infection . J Leukoc Biol.;82(2):253-8.
6. Takahara K et al., 2004. Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin C-type lectins. Int Immunol. 16:819-829.
7. den Dunnen J. et al., 2008. Innate signaling by C-type lectin DC-SIGN dictates immune responses. Cancer Immunol Immunother. 26:605-610.
8. Van Asbeck et al., 2008. Mannose binding lectin plays a crucila role in innate immunity against yeast by enhanced comploment activation and enhanced uptake of polymorphonuclear cells. BMC Microbiol. 8:229.
9. Ji X. et al., 2005. Mannose-binding lectin binds to Ebola and Marburg envelope glycoproteins, resulting in blocking of virus interaction with DC-SIGN and complementmediated virus neutralization. J Gen Virol. 86; 2535-2542.
10. Brown GD. 2008. Sensing necrosis with Mincle. Nature Immunol. 9:1099-1100.