TIR3 regulates mycobacterial RNA-induced IL-10 production through the PI3K/AKT signaling pathway
TIR3 regulates mycobacterial RNA-induced IL-10 production through the PI3K/AKT signaling pathway
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TLR3 通过 PI3K/AKT 信号通路调节分枝杆菌 RNA 诱导的 IL-10 产生
DOI：
10.1016/j.cellsig.2014.01.015
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发表时间：
2014-05-01
影响因子：
4.8
通讯作者：
Ge, Baoxue
中科院分区：
文献类型：
--
作者：
Bai, Wenjuan;Liu, Haipeng;Ge, Baoxue
针对结核分枝杆菌 (Mtb) 感染的细胞因子诱导对于病原体控制至关重要，其途径是 (i) 介导先天免疫效应器功能和 (ii) 指导特异性适应性免疫。 IL-10是一种重要的抗炎细胞因子，参与结核病（TB）的发病机制。在这里，我们证明 TLR3 是细胞外病毒或宿主 RNA 的传感器，具有源自感染或受损细胞的稳定干结构，对于 Mtb 诱导的 IL-10 产生至关重要。牛分枝杆菌卡介苗 (BCG) 感染后，TLR3(-/-) 巨噬细胞表达较低的 IL-10，但产生较高的 IL-12p40，同时伴随 Ser473 处 Ala 磷酸化的减少。与对照组相比，BCG 感染的 TLR3(-/-) 小鼠表现出 IL-10 表达降低但 IL-12 表达升高。此外，在BCG感染的TLR3(-/-)小鼠中观察到脾脏Th1细胞数量增多，肺部细菌负荷和组织损伤减少。最后，BCG RNA 通过 TLR3 介导的 PI3K/AKT 激活诱导巨噬细胞中的 IL-10。我们的研究结果表明，TLR3 介导的调节在涉及分枝杆菌 RNA 的分枝杆菌感染发病机制中发挥着关键作用，分枝杆菌 RNA 通过 PI3K/AKT 信号通路诱导 IL-10。 (C) 2014 爱思唯尔公司保留所有权利。
Cytokine induction in response to Mycobacterium tuberculosis (Mtb) infection is critical for pathogen control, by (i) mediating innate immune effector functions and (ii) instructing specific adaptive immunity. IL-10 is an important anti-inflammatory cytokine involved in pathogenesis of tuberculosis (TB). Here, we show that TLR3, a sensor of extracellular viral or host RNA with stable stem structures derived from infected or damaged cells, is essential for Mtb-induced IL-10 production. Upon Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, TLR3(-/-) macrophages expressed lower IL-10 but higher IL-12p40 production, accompanied by reduced phosphorylation of Ala at Ser473. BCG-infected TLR3(-/-) mice exhibited reduced IL-10 but elevated IL-12 expression compared to controls. Moreover, higher numbers of splenic Thl cells and reduced pulmonary bacterial burden and tissue damage were observed in BCG-infected TLR3(-/-) mice. Finally, BCG RNA induced IL-10 in macrophages via TLR3-mediated activation of PI3K/AKT. Our findings demonstrate a critical role of TLR3-mediated regulation in the pathogenesis of mycobacterial infection involving mycobacterial RNA, which induces IL-10 through the PI3K/AKT signaling pathway. (C) 2014 Elsevier Inc All rights reserved.