Toll-Like Receptor 2 Mediates In Vivo Pro- and Anti-inflammatory Effects of Mycobacterium Tuberculosis and Modulates Autoimmune Encephalomyelitis.
Toll-Like Receptor 2 Mediates In Vivo Pro- and Anti-inflammatory Effects of Mycobacterium Tuberculosis and Modulates Autoimmune Encephalomyelitis.
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DOI：
10.3389/fimmu.2016.00191
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发表时间：
2016
影响因子：
7.3
通讯作者：
Ria F
中科院分区：
文献类型：
--
作者：
Piermattei A;Migliara G;Di Sante G;Foti M;Hayrabedyan SB;Papagna A;Geloso MC;Corbi M;Valentini M;Sgambato A;Delogu G;Constantin G;Ria F
分枝杆菌在人体和实验病理中表现出促炎和抗炎作用。通过利用先前表征的Tlr2变体（Met82Ile），我们发现这两种效应都是由toll样受体2 （Tlr2）介导的。Tlr2 82ile促进了自身特异性促炎极化以及ag特异性FoxP3+ treg的扩增，而Tlr2 82met则损害treg的扩增并减少IFN-γ和IL-17促炎细胞因子的产生。与Tlr1或Tlr6的优先二聚化不能解释这些差异。因此，我们发现Tlr2变体Met82Ile修饰了肽聚糖的结合袋，并直接参与了糖和钙粘蛋白的假设结合袋。不同的促炎和抗炎作用影响实验性自身免疫性脑脊髓炎的严重程度、缓解程度和中枢神经系统内病变的分布。因此，Tlr2在体内具有双重功能，作为细菌产物在平衡促炎性和抗炎性免疫反应中的中介作用。
Mycobacteria display pro- and anti-inflammatory effects in human and experimental pathology. We show here that both effects are mediated by Toll-like receptor 2 (Tlr2), by exploiting a previously characterized Tlr2 variant (Met82Ile). Tlr2 82ile promoted self-specific proinflammatory polarization as well as expansion of ag-specific FoxP3+ Tregs, while Tlr2 82met impairs the expansion of Tregs and reduces the production of IFN-γ and IL-17 proinflammatory cytokines. Preferential dimerization with Tlr1 or Tlr6 could not explain these differences. In silico, we showed that Tlr2 variant Met82Ile modified the binding pocket for peptidoglycans and participated directly to a putative binding pocket for sugars and cadherins. The distinct pro- and anti-inflammatory actions impacted severity, extent of remission, and distribution of the lesions within the central nervous system of experimental autoimmune encephalomyelitis. Thus, Tlr2 has a janus function in vivo as mediator of the role of bacterial products in balancing pro- and anti-inflammatory immune responses.