Association of SIGNR1 with TLR4–MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria

Nagaoka, Koji; Takahara, Kazuhiko; Tanaka, Kay; Yoshida, Hideo; Steinman, Ralph M.; Saitoh, Shin-ichiro; Akashi-Takamura, Sachiko; Miyake, Kensuke; Kang, Young Sun; Park, Chae Gyu; Inaba, Kayo

doi:10.1093/intimm/dxh264

Cited by 76 publications

(65 citation statements)

References 44 publications

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“…Previous in vitro work has demonstrated that SIGN-R1 associates with the TLR4-MD2 complex on the plasma membrane and SIGN-R1 binds E. coli LPS, enhancing both TLR4 oligomerization and downstream signaling via IkB-a degradation (12). It was shown that anti-SIGN-R1 Ab treatment blocks cytokine production from pMfs (12).…”

Section: Discussionmentioning

confidence: 99%

“…Following binding of PAMPs by DC-SIGN, a signaling pathway is initiated that modulates TLR3-, 4-and -5-induced cytokine responses (9). Interestingly, a member of a family of DC-SIGN homologs described in mice, SIGN-related 1 (R1)/CD209b (10,11), has also been shown to interact with the TLR signaling system, with SIGN-R1 associating with the TLR4-MD2 complex to enhance signal transduction in response to LPS in Gram-negative bacteria in vitro (12). Unlike DC-SIGN, SIGN-R1 is not expressed on DCs but is on splenic marginal zone, lymph node, and peritoneal macrophages (pMfs) (13)(14)(15) and can recognize glycans from different pathogens (16).…”

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confidence: 99%

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C-Type Lectin SIGN-R1 Has a Role in Experimental Colitis and Responsiveness to Lipopolysaccharide

Saunders

Barlow

Walsh

et al. 2010

The Journal of Immunology

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Pathogen recognition receptors (PRRs) function to maintain the balance between controlled responses to pathogens and uncontrolled innate immune activation leading to inflammation. In the context of commensal bacteria and the etiology of inflammatory bowel disease, although a role for the TLRs is known, there is a less defined function for C-type lectin receptors (CLRs). We demonstrate that mice deficient (−/−) in the CLR specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) (CD209b) have reduced susceptibility to experimental colitis, with a reduction in the disease severity, colon damage, and levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6. To determine whether SIGN-R1−/− mice had a systemic defect in innate activation, we examined the responsiveness of macrophages from SIGN-R1−/− mice to TLR ligands. SIGN-R1−/− peritoneal macrophages, but not bone marrow-derived macrophages, have a specific defect in IL-1β and IL-18 production, but not other cytokines, in response to the TLR4 ligand LPS. In vivo SIGN-R1−/− mice had significantly reduced susceptibility to LPS-induced shock. To address the synergistic relationship between SIGN-R1 and TLR4 in the context of experimental colitis, SIGN-R1/TLR4−/− mice were generated. SIGN-R1/TLR4−/− mice displayed reduced susceptibility to experimental colitis relative to severity of disease observed in wild-type or TLR4−/− mice. The in vivo use of a blocking mAb confirmed a functional role for SIGN-R1 in LPS-induced shock and experimental colitis. These data indicate a role for SIGN-R1 in the regulation of inflammation in a model of experimental colitis and illustrate that SIGN-R1 is a critical innate factor in response to LPS.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

C-Type Lectin SIGN-R1 Has a Role in Experimental Colitis and Responsiveness to Lipopolysaccharide

Saunders

Barlow

Walsh

et al. 2010

The Journal of Immunology

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“…HEK293T cells, the mouse monocytic cell line RAW264.7 cells and RAW-transfectants (RAW-SIGNR1, RAW-control and RAW-SIGNR1Dcyto cells) were maintained as described previously [26]. Expression levels of SIGNR1 and Dectin-1 of these transfectants were analyzed with biotinylated anti-SIGNR1 clone 22D1 [28] with PE-streptavidine and anti-Dectin-1 clone 2A11 (AbD Serotec, Oxford, UK) with PE-anti-rat IgG, respectively.…”

Section: Cells and Microbesmentioning

confidence: 99%

“…SIGNR1 recognizes not only various polysaccharides, such as dextran and mannan, but also lipopolysaccharides (LPS) from Gram-negative bacteria (E. coli and Salmonella typhimurium) [23]. The physical association of SIGNR1 with the TLR4-MD-2 complex on the cell surface accelerates TLR4 oligomerization upon recognition of the non-reductive end of LPS core on Gram-negative bacteria [26]. In addition, SIGNR1 on resident peritoneal macrophages (rpMf) and SIGNR1-transfected RAW264.7 cells recognizes zymosan and heat-killed (HK) C. albicans together with Dectin-1 [23,24].…”

Section: Introductionmentioning

confidence: 99%

C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1

et al. 2011

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We investigated the role of SIGNR1 in the recognition of Candida albicans and the subsequent cellular oxidative burst response. Soluble SIGNR1 (sSIGNR1) tetramer bound equally to zymosan and both heat-killed (HK) and live C. albicans in an EDTA-sensitive manner, whereas sDectin-1 tetramer predominantly bound to zymosan and HK-microbes in an EDTA-independent manner. In cellular response, enhanced oxidative burst was observed in RAW264.7 cells expressing SIGNR1 (RAW-SIGNR1) compared with RAW-control cells upon stimulation with HK-C. albicans and zymosan. This response was independent of TLR2 and the cytosolic portion of SIGNR1 but dependent on the recognition by SIGNR1 via carbohydrate recognition domain. Antagonistic laminarin and anti-Dectin-1 mAb cooperatively reduced the response with mannan and anti-SIGNR1 mAb, respectively, although they had no effect by themselves. Moreover, oxidative response and bactericidal activity largely relied on Syk-mediated signaling. RAW-SIGNR1 cells not only captured microbes more efficiently but also showed higher responses than RAW-control cells. Similar enhanced responses were observed in SIGNR-1-expressing resident peritoneal M/. Interestingly, Dectin-1 was recruited to the phagosomal membrane upon the stimulation and physically associated with SIGNR1. These results suggest that SIGNR1 plays a significant role in inducing oxidative response to C. albicans by Syk-dependent signaling, possibly through Dectin-1.Key words: C. albicans . Dectin-1 . Macrophages . SIGNR1 . TLR2 IntroductionInnate immunity is a crucial host defense system that eliminates pathogens as they initiate an infection and leads to the subsequent initiation of the adaptive immune response [1]. The system consists of germline-encoded genes, i.e. toll-like receptors (TLRs) [2] [8][9][10][11][12]. Microbe-mediated stimulation of Dectin-1 results in cellular oxidative burst and cytokine production through its ITAM and the Syk kinase pathway [13,14]. In addition, Dectin-1 has been shown to function collaboratively with TLR2 to stimulate cytokine production [15] and Th17/Treg induction [16].hDC-SIGN recognizes mannose and fucose moieties in the surface of a variety of microbes and viruses, such as Mycobacteria, Leishmania, Salmonella, Candida species, HIV, HCV, dengue virus, CMV, Ebola virus and Sindbis virus (refer to [17]). However, pathogens, i.e. HIV and HCV, have also found ways to subvert and use hDC-SIGN to their advantage [18,19]. Mycobacterium tuberculosis and HIV also target hDC-SIGN in order to upregulate DC production of the immunosuppressive cytokine IL-10 through Raf-1 kinase activation, which induces acetylation of the NF-kB p65 subunit in the presence of co-signaling from TLR4 [20].Mice have eight hDC-SIGN homologues [21,22]. One of these homologues, SIGNR1, has been shown to be expressed on particular Mf subsets in the marginal zone of the spleen, medulla of the lymph nodes and the peritoneal cavity [23][24][25] and to possess mannosebinding activities like hDC-SIGN. SIGNR1 recognizes not only vari...

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“…Although the detailed signaling pathways triggered by OMLs are still unknown, it is possible that this activity is associated with both CLR and TLR signaling. It has been shown that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate immune responses (47). CD8 + cells isolated from stimulated spleen cells of OML/OVA-treated mice showed cytotoxicity against E.G7-OVA tumor cells (OVA-transfected EL4 cells), which present OVA peptide as a model tumor antigen on MHC class I, but not against parental EL4 tumor cells (15).…”

Section: E Involvement Of C-type Lectin Receptors (Clrs) In Oml Uptamentioning

confidence: 99%

Development of Novel Carbohydrate-Coated Liposome-Based Vaccines

Kojima

Kawauchi

Ishii

2011

TIGG

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Antigen delivery systems are important for inducing and modifying immune responses. A key to development of vaccines is the ability to deliver antigens to antigenpresenting cells (APCs) more efficiently and to induce subsequent activation of T cell-mediated immunity. Thus, strategies that target APCs and modulate APC functions in vivo have significant implications for vaccine design. We have demonstrated that oligomannose-coated liposomes (OMLs), which consist of DPPC, cholesterol, Man3-DPPE at a molar ratio of 10:10:1, can induce strong cellular immunity. In this review, we discuss OMLs as novel antigen-delivery vehicles that also have a strong adjuvant effect on induction of Th1 immune responses and CTLs specific for the encased antigen. This property of OMLs is due to their ability to assist specific cellular uptake in vivo and to promote subsequent APC maturation, presentation of antigens on APCs, preferential secretion of IL-12 from APCs, and migration of APCs into lymphoid tissues from peripheral tissues. Administration of an OML-based vaccine can eliminate an established tumor, inhibit elevation of the serum level of IgE against an allergen, and prevent progression of some protozoan infections in mouse models. In addition, OMLs with an encased antigen are able to induce antigen-specific CTLs in PBMCs obtained from patients. These feasibility studies of OML-based vaccines have revealed their potential for clinical use in vaccination for diseases in which CTLs and/or Th1 cells act as effector cells.

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Association of SIGNR1 with TLR4–MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria

Cited by 76 publications

References 44 publications

C-Type Lectin SIGN-R1 Has a Role in Experimental Colitis and Responsiveness to Lipopolysaccharide

C-Type Lectin SIGN-R1 Has a Role in Experimental Colitis and Responsiveness to Lipopolysaccharide

C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1

Development of Novel Carbohydrate-Coated Liposome-Based Vaccines

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