HMGB1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR4/MyD88-dependent signaling pathway.
HMGB1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR4/MyD88-dependent signaling pathway.
复制标题
HMGB1易位和释放通过TLR4/MYD88依赖性信号通路介导小鼠烟雾诱导的肺部炎症。
DOI：
10.1091/mbc.e16-02-0126
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发表时间：
2017-01-01
影响因子：
3.3
通讯作者：
He S
中科院分区：
文献类型：
--
作者：
Cheng Y;Wang D;Wang B;Li H;Xiong J;Xu S;Chen Q;Tao K;Yang X;Zhu Y;He S
香烟烟雾(CS)增加TLR4介导的信号转导上调，并诱导肺内TLR4依赖性炎症。CS暴露诱导的HMGB1移位和HMGB1的释放控制CS诱导的炎症反应。MGB1诱导TLR4介导的促炎细胞因子的产生，并激活NF-κB和JNKp38通路。我们进行了研究，以确定高迁移率族蛋白1(HMGB1)在香烟烟雾(CS)诱导的肺部炎症中的作用。小鼠每天4次吸烟3d后，Toll样受体4(Toll-like Receptor 4，TLR4)的表达及TLR4介导的信号转导显著上调，HMGB1在肺上皮细胞中从胞核移位到胞浆，然后释放到肺细胞外间隙。在CS暴露时，肺组织和支气管肺泡灌洗液中炎性细胞募集和促炎细胞因子的产生显著增加，这些作用依赖于TLR4信号通路。抑制HMGB1可降低CS诱导的炎症反应，而外源性HMGB1可加重野生型小鼠肺组织中JNK、p38和IκBα的磷酸化，但对TLR4基因敲除小鼠无明显影响。阻断TLR4作用或TLR4基因敲除可显著抑制HMGB1诱导的小鼠气管上皮细胞和肺组织促炎细胞因子的产生。此外，MyD88基因缺失抑制了JnK、p38和IκBα的磷酸化，这种作用与CS刺激抑制MTE细胞和肺组织产生肿瘤坏死因子-α和IL-1β有关。因此，HMGB1通过依赖于TLR4MyD88的信号通路激活NF-κB和JNKp38通路，从而在CS暴露的肺组织中诱导炎症反应。
Cigarette smoke (CS) increases up-regulation of TLR4-mediated signaling and induces TLR4-dependent inflammation in lungs. CS exposure–induced HMGB1 translocation and release of HMGB1 controls CS-induced inflammatory response. MGB1 induces TLR4-mediated proinflammatory cytokine production and activates NF-κB and JNK/p38 pathways. We performed studies to determine the role of high-mobility group box 1 (HMGB1) in cigarette smoke (CS)–induced pulmonary inflammation. After mice were exposed to five cigarettes four times a day for 3 d, toll-like receptor 4 (TLR4) expression and TLR4-mediated signaling were significantly up-regulated, and HMGB1 had translocated from the nucleus to the cytoplasm in lung epithelial cells and then been released into the extracellular lung space. On CS exposure, inflammatory cell recruitment and proinflammatory cytokine production were significantly increased in lung tissue and bronchoalveolar lavage, and these effects depended on the TLR4 signaling pathway. HMGB1 inhibition decreased the CS-induced inflammatory response, whereas treatment with exogenous HMGB1 aggravated the damage and increased the phosphorylation of JNK, p38, and IκBα in the lungs of wild-type mice but not in TLR4-knockout mice. Blockade of TLR4 action or TLR4 knockout significantly inhibited HMGB1-induced proinflammatory cytokine production in mouse tracheal epithelial (MTE) cells and lung tissues. In addition, a MyD88 deficiency inhibited JNK, p38, and IκBα phosphorylation, and this effect was associated with the suppressed production of TNF-α and IL-1β in MTE cells and lung tissues in response to CS stimulation. Thus HMGB1 activates the NF-κB and JNK/p38 pathways through TLR4/MyD88-dependent signaling and induces an inflammatory response in lungs exposed to CS.