Dectin-2 Recognizes Mannosylated O-antigens of Human Opportunistic Pathogens and Augments Lipopolysaccharide Activation of Myeloid Cells.
Dectin-2 Recognizes Mannosylated O-antigens of Human Opportunistic Pathogens and Augments Lipopolysaccharide Activation of Myeloid Cells.
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DOI：
10.1074/jbc.m116.741256
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发表时间：
2016-08-19
期刊：
影响因子：
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通讯作者：
Kawasaki N
中科院分区：
文献类型：
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作者：
Wittmann A;Lamprinaki D;Bowles KM;Katzenellenbogen E;Knirel YA;Whitfield C;Nishimura T;Matsumoto N;Yamamoto K;Iwakura Y;Saijo S;Kawasaki N
脂多糖由一个相对保守的类脂A区和核心低聚糖组成，以及一个高度可变的O抗原多糖区。虽然已知类脂A与Toll样受体4(TLR4)-髓系分化因子2(MD2)复合体结合，但O-抗原的作用尚不清楚。在这里，我们报道了树突状细胞相关的C型凝集素-2(Dectin-2)与在含有[-Man-α1，3-Man-α1，2-Man-α1，2-Man-α1，2-Man-α1，3-].重复单位的人类机会致病菌Hafnia alvei PCM1223中发现的甘露糖化O抗原之间的一种新的分子相互作用肺泡杆菌脂多糖诱导小鼠骨髓来源的树突状细胞(BM-DC)产生更高水平的肿瘤坏死因子α和IL-10，与具有重复[-Gal-α1，6-Gal-α1，4-[Glc-β1，3]GalNAc-α1，3-GalNAc-β1，3-].的肠炎沙门氏菌O66脂多糖相比在基于细胞的报告实验中，Dectin-2被证明能够识别肺泡杆菌内毒素。这种结合被甘露糖苷酶和Dectin-2糖结合域的突变所抑制，表明H.alvei LPS是Dectin-2的一种新的糖链配体。由于Dectin-2基因敲除的BM-DC不能促进细胞因子的产生，因此这种细胞因子的产生是依赖Dectin-2的。Dectin-2和TLR4之间的受体相互作用涉及脾酪氨酸激酶(Syk)激活和受体并置等事件。此外，来自大肠杆菌O9a的另一种甘露糖化的内毒素也能与Dectin-2结合，并增强BM-DC的TLR4活性。综上所述，这些数据表明，来自几种革兰氏阴性细菌的甘露糖化O抗原通过与Dectin-2相互作用增强了TLR4的反应。
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-α1,3-Man-α1,2-Man-α1,2-Man-α1,2-Man-α1,3-]. H. alvei LPS induced higher levels of TNFα 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-α1,6-Gal-α1,4-[Glc-β1,3]GalNAc-α1,3-GalNAc-β1,3-]. 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.