期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 34, 页码 17629-17638出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.741256
关键词
immunology; lectin; lipopolysaccharide (LPS); polysaccharide; Toll-like receptor 4 (TLR4)
资金
- BBSRC [BBS/E/F/00044486]
- Big C cancer research grant
- European Union
- Biotechnology and Biological Sciences Research Council [BBS/E/F/00044486, BBS/E/F/00042723] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [15H05787] Funding Source: KAKEN
- BBSRC [BBS/E/F/00044486, BBS/E/F/00042723] Funding Source: UKRI
LPS consists of a relatively conserved region of lipid A and core oligosaccharide and a highly variable region of O-antigen polysaccharide. Whereas lipid A is known to bind to the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, the role of the O-antigen remains unclear. Here we report a novel molecular interaction between dendritic cell-associated C-type lectin-2 (Dectin-2) and mannosylated O-antigen found in a human opportunistic pathogen, Hafnia alvei PCM 1223, which has a repeating unit of [-Man-1,3-Man-1,2-Man-1,2-Man-1,2-Man-1,3-]. H. alvei LPS induced higher levels of TNF and IL-10 from mouse bone marrow-derived dendritic cells (BM-DCs), when compared with Salmonella enterica O66 LPS, which has a repeat of [-Gal-1,6-Gal-1,4-[Glc-1,3]GalNAc-1,3-GalNAc-1,3-]. In a cell-based reporter assay, Dectin-2 was shown to recognize H. alvei LPS. This binding was inhibited by mannosidase treatment of H. alvei LPS and by mutations in the carbohydrate-binding domain of Dectin-2, demonstrating that H. alvei LPS is a novel glycan ligand of Dectin-2. The enhanced cytokine production by H. alvei LPS was Dectin-2-dependent, because Dectin-2 knock-out BM-DCs failed to do so. This receptor cross-talk between Dectin-2 and TLR4 involved events including spleen tyrosine kinase (Syk) activation and receptor juxtaposition. Furthermore, another mannosylated LPS from Escherichia coli O9a also bound to Dectin-2 and augmented TLR4 activation of BM-DCs. Taken together, these data indicate that mannosylated O-antigens from several Gram-negative bacteria augment TLR4 responses through interaction with Dectin-2.
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