HMGB1 regulates T helper 2 and T helperl7 cell differentiation both directly and indirectly in asthmatic mice
HMGB1 regulates T helper 2 and T helperl7 cell differentiation both directly and indirectly in asthmatic mice
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DOI：
10.1016/j.molimm.2018.02.014
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发表时间：
2018-05-01
影响因子：
3.6
通讯作者：
Yang, Jiong
中科院分区：
文献类型：
--
作者：
Li, Ruiting;Wang, Jing;Yang, Jiong
Th（辅助性T细胞）2反应是过敏性哮喘的特征，而Th 17细胞参与更严重的哮喘。近年来的研究表明，高迁移率族蛋白B1（High mobility group box 1 protein，HMGB 1）在哮喘气道炎症及Th 2、Th 17炎症反应中起着重要的调节作用。HMGB 1可与Toll样受体（TLR）2和4以及晚期糖基化终产物受体（TLR）相互作用，激活NF-κ B（核因子κ B）信号通路并诱导下游炎症介质的释放。Th细胞和树突状细胞都表达TLR 2、TLR 4和TLR 4受体。因此，我们推测HMGB 1可能通过直接和间接机制调节哮喘患者Th 2、Th 17细胞的分化。建立卵清蛋白（OVA）诱导的小鼠哮喘模型。在每次攻击前30分钟，向OVA致敏小鼠施用抗HMGB 1抗体或rHMGB 1。对于体外研究，用或不用rHMGB 1和/或抗HMGB 1抗体刺激磁性分离的CD 4（+）初始T细胞。将用或不用rHMGB 1和/或抗HMGB 1抗体刺激的BMDC（骨髓来源的树突状细胞）与CD 4（+）初始T细胞共培养。我们的研究表明，给予rHMGB 1可加重哮喘小鼠气道炎症和粘液产生，诱导Th 2、Th 17极化，抗HMGB 1抗体可减弱哮喘的特征性特征，阻断Th 2、Th 17炎症反应。HMGB 1可通过激活CD 4（+）naive T细胞的TLR 2、TLR 4、RAGE-NF-kappa B信号通路，直接作用于naive T细胞，诱导Th 2、Th 17细胞分化。HMGB 1还可通过激活TLR 2、TLR 4、RAGE-NF-kappa B信号通路间接促进DC向Th 2、Th 17细胞分化，介导DC的成熟和抗原提呈能力。
The Th (T helper) 2 response is characteristic of allergic asthma, and Th17 cells are involved in more severe asthma. Recent studies demonstrated that HMGB1 (High mobility group box 1 protein) regulates airway inflammation and the Th2, Th17 inflammatory response in asthma. HMGB1 can interact with Toll-like receptors (TLR) 2 and 4, and the receptor for advanced glycation end products (RAGE), activating the NF-kappa B (nuclear factor kappa B) signaling pathway and inducing the release of downstream inflammatory mediators. Both Th cells and dendritic cells express TLR2, TLR4, and RAGE receptors. Therefore, we speculate that HMGB1 could regulate the differentiation of Th2, Th17 cells in asthma through direct and indirect mechanisms. An ovalbumin (OVA)-induced mouse asthmatic model was established. Anti-HMGB1 antibody or rHMGB1 was administered to OVA-sensitized mice 30 min prior to each challenge. For in vitro studies, magnetically separated CD4(+) naive T cells were stimulated with or without rHMGB1 and/or anti-HMGB1 antibody. BMDCs (bone marrow-derived dendritic cells)-stimulated with or without rHMGB1 and/or anti-HMGB1 antibody were cocultured with CD4(+) naive T cells. Our study showed that administration of rHMGB1 aggravated airway inflammation and mucus production, and induced Th2, Th17 polarization in asthmatic mice, and that anti-HMGB1 antibody weakened characteristic features of asthma and blocked the Th2, Th17 inflammatory responses. HMGB1 could directly act on naive T cells to induce differentiation of Th2, Th17 cells in vitro through activating the TLR2, TLR4, RAGE-NF-kappa B signal pathway in CD4(+) naive T cells. HMGB1 could also indirectly promote Th2, Th17 differentiation via activating the TLR2, TLR4, RAGE-NF-kappa B signal pathway in DCs to mediate their maturation and antigen-presenting ability in vitro.