Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria.
ABSTRACT SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (Mphi) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC-dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of IkappaB-alpha after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4-MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate M responses.
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ABSTRACT: Effective immune responses depend on the recognition of pathogens by dendritic cells (DCs) through pattern recognition receptors (PRRs). These receptors induce specific signaling pathways that lead to the induction of immune responses against the pathogens. It is becoming evident that C-type lectins are also important PRRs. In particular, the C-type lectin DC-SIGN has emerged as a key player in the induction of immune responses against numerous pathogens by modulating TLR-induced activation. Recent reports have begun to elucidate the molecular mechanisms underlying these immune responses. Upon pathogen binding, DC-SIGN induces an intracellular signaling pathway with a central role for the serine/threonine kinase Raf-1. For several pathogens that interact with DC-SIGN, including Mycobacterium tuberculosis and HIV-1, Raf-1 activation leads to acetylation of NF-kappaB subunit p65, which induces specific gene transcription profiles. In addition, other DC-SIGN-ligands induce different signaling pathways downstream of Raf-1, indicating that DC-SIGN-signaling is tailored to the pathogen. In this review we will discuss in detail the current knowledge about DC-SIGN signaling and its implications on immunity.Cancer Immunology and Immunotherapy 12/2008; 58(7):1149-57. · 3.70 Impact Factor
Article: The C-type lectin SIGNR1 binds Schistosoma mansoni antigens in vitro, but SIGNR1-deficient mice have normal responses during schistosome infection.[show abstract] [hide abstract]
ABSTRACT: The de novo immune response to infectious organisms arises from the innate recognition of pathogen-associated molecular patterns (PAMPs) by the host's pattern recognition receptors (PRRs). As the generation of type 2 cytokine responses by the human trematode parasite Schistosoma mansoni is glycan mediated, there is a particular potential role for a C-type lectin receptor (CLR) to mediate the innate recognition of schistosome PAMPs. One such CLR, dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209), has been shown to recognize glycans expressed by S. mansoni eggs. We show that SIGNR1 (SIGN-related 1; CD209b), a murine homologue of DC-SIGN that is expressed on macrophages, also binds both schistosome-soluble egg antigens and worm antigens in vitro. The generation of schistosome egg-induced pulmonary egg granulomas was not altered in SIGNR1-deficient mice. Following S. mansoni infection, the SIGNR1-deficient mice had an unaltered phenotype with an intact immunological response and no difference in pathology. In this study we demonstrate that although SIGNR1 recognizes S. mansoni antigens in vitro, this CLR is redundant during infection. This study highlights the finding that although there was binding of SIGNR1 to immunogenic factors produced in the S. mansoni life cycle, this recognition does not translate to a functional in vivo role for the PRR during infection.Infection and immunity 12/2008; 77(1):399-404. · 4.21 Impact Factor
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ABSTRACT: Autoimmune and autoinflammatory diseases represent a significant health burden, especially in Western societies. For the majority of these diseases, no cure exists. Recently, research on parasitic worms (helminths) has demonstrated great potential for whole worms, their eggs or their excretory/secretory proteins in down-regulating inflammatory responses both in vitro and in vivo, in various disease models and, in some cases, even in clinical trials. The worms are thought to induce Th2 and regulatory T cells, interfere with Toll-like receptor (TLR) signaling and to down-regulate Th17 and Th1 responses. The molecular mechanisms underlying the worms' ability to modulate the host immune response are not well understood, and many hypotheses have been proposed to explain the observed immune modulation. Increasing evidence suggests that carbohydrate structures (glycans), for example, phosphorylcholine-modified glycans or Galbeta1-4(Fucalpha1-3)GlcNAc- (Lewis X, Le(X)) containing glycans, expressed by the worms contribute to these modulating properties by their interaction with antigen presenting cells. Helminths express a broad variety of protein- and lipid-linked glycans on their surface and on secretory products. These glycans differ in amount and composition and several of these structures are species specific. However, worms also express glycan antigens that are found in a wide variety of different species. Some of these "common" worm glycans are particularly interesting with regard to regulating host responses, because they have the potential to interact with C-type lectins on dendritic cells and thereby may interfere with T-cell polarization. Helminths and helminth-derived molecules form a novel and promising group of therapeutics for autoinflammatory diseases. However, much has to be learned about the molecular mechanisms behind the helminth-mediated antiinflammatory properties. This review will describe some of the emerging evidence in selected disease areas as well as discuss the putative role of glycans in helminth-mediated immunosuppression.International Union of Biochemistry and Molecular Biology Life 04/2010; 62(4):303-12. · 3.51 Impact Factor