Engagement of Toll‐like receptor 2 enhances interleukin (IL)‐17+ autoreactive T cell responses via p38 mitogen‐activated protein kinase signalling in dendritic cells
Engagement of Toll‐like receptor 2 enhances interleukin (IL)‐17+ autoreactive T cell responses via p38 mitogen‐activated protein kinase signalling in dendritic cells
复制标题
DOI：
10.1111/cei.12405
复制
发表时间：
2014-11
影响因子：
4.6
通讯作者：
R. Wei;Lijie Dong;Q. Xiao;Deming Sun;Xue Li;Hong Nian
中科院分区：
文献类型：
--
作者：
R. Wei;Lijie Dong;Q. Xiao;Deming Sun;Xue Li;Hong Nian
有必要对体内单个Toll样受体（TLR）进行功能分析，以了解它们如何塑造葡萄膜炎中涉及的眼部炎症。在这项研究中，我们探讨了TLR-2激动剂对实验性自身免疫性葡萄膜炎（EAU）中自身反应性辅助性T细胞17型（Th 17）反应的作用和机制。肽聚糖（PGN）（一种特异性TLR-2激动剂）治疗可显著增加EAU小鼠中Th 17谱系基因白细胞介素（IL）-17 A、IL-21和RAR相关孤儿受体（ROR）γt的mRNA水平，并促进抗原特异性Th 17应答。PGN和光感受器间类维生素A结合蛋白肽（IRBP 161 -180）的混合物可以在不存在完全弗氏佐剂（CFA）的情况下有效地诱导EAU。PGN治疗还增强了体内活化的抗原特异性Th 17细胞的致病活性。PGN显著增加树突状细胞（DCs）产生IL-1β、IL-6和IL-23，并增强其促进IL-17+葡萄膜原性T细胞的能力。PGN-DC的增强的免疫刺激活性取决于p38活化。抑制p38丝裂原活化蛋白激酶（MAPK）活性可显著降低PGN-DCs刺激的IL-17基因表达和抗原特异性Th 17应答。我们的研究结果表明，PGN治疗通过增强DC的免疫刺激活性显著促进IL-17+葡萄膜原性T细胞应答。这种作用可能是介导的，至少部分是通过激活的p38信号通路在DC。
Functional analysis of single Toll‐like receptors (TLRs) in vivo is necessary to understand how they shape the ocular inflammation involved in uveitis. In this study we explored the role and mechanisms of TLR‐2 agonists on the autoreactive T helper type 17 (Th17) response in experimental autoimmune uveitis (EAU). Treatment by peptidoglycan (PGN), a specific TLR‐2 agonist, remarkably increased mRNA levels of Th17‐lineage genes interleukin (IL)‐17A, IL‐21 and RAR‐related orphan receptor (ROR)γt and promoted antigen‐specific Th17 response in EAU mice. A mixture of PGN and interphotoreceptor retinoid‐binding protein peptide (IRBP161–180) could effectively induce EAU in the absence of complete Freund's adjuvant (CFA). PGN treatment also enhanced the pathogenic activities of activated antigen‐specific Th17 cells in vivo. PGN significantly increased the production of IL‐1β, IL‐6 and IL‐23 of dendritic cells (DCs) and enhanced their ability to promote IL‐17+ uveitogenic T cells. Enhanced immunostimulatory activities of PGN‐DCs depend upon p38 activation. Inhibition of p38 mitogen‐activated protein kinase (MAPK) activity dramatically decreased IL‐17 gene expression and antigen‐specific Th17 responses stimulated by PGN‐DCs. Our findings suggest that PGN treatment dramatically promotes the IL‐17+ uveitogenic T cell responses via enhancing the immunostimulatory activities of DCs. This effect may be mediated, at least in part, by activation of the p38 signalling pathway in DCs.