Chen Xiangyu, Li Lingyun, Khan Muhammad Noman, Shi Lifeng, Wang Zhongyan, Zheng Fang, Gong Feili, Fang Min
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
2 Department of Immunology, Dalian Medical University, P. R. China.
Innate Immun. 2016 Nov;22(8):696-705. doi: 10.1177/1753425916669862. Epub 2016 Sep 27.
In inflammatory bowel diseases (IBD), high mobility group box 1 (HMGB1), as an endogenous inflammatory molecule, can promote inflammatory cytokines secretion by acting on TLR2/4 resulting in tissue damage. The underlying mechanisms remain unclear. Here we report a novel role of HMGB1 in controlling the maintenance and function of intestine-resident group-3 innate lymphoid cells (ILC3s) that are important innate effector cells implicated in mucosal homeostasis and IBD pathogenesis. We showed that mice treated with anti-HMGB1 Ab, or genetically deficient for TLR2 or TLR4 mice, displayed reduced intestinal inflammation. In these mice, the numbers of colonic ILC3s were significantly reduced, and the levels of IL-17 and IL-22 that can be secreted by ILC3s were also decreased in the colon tissues. Furthermore, HMGB1 promoted DCs via TLR2/4 signaling to produce IL-23, activating ILC3s to produce IL-17 and IL-22. Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.
在炎症性肠病（IBD）中，高迁移率族蛋白B1（HMGB1）作为一种内源性炎症分子，可通过作用于Toll样受体2/4（TLR2/4）促进炎性细胞因子的分泌，从而导致组织损伤。其潜在机制仍不清楚。在此，我们报告了HMGB1在控制肠道固有3型天然淋巴细胞（ILC3s）的维持和功能方面的新作用，ILC3s是参与黏膜稳态和IBD发病机制的重要天然效应细胞。我们发现，用抗HMGB1抗体处理的小鼠，或TLR2或TLR4基因缺陷的小鼠，肠道炎症减轻。在这些小鼠中，结肠ILC3s的数量显著减少，结肠组织中ILC3s分泌的IL-17和IL-22水平也降低。此外，HMGB1通过TLR2/4信号通路促进树突状细胞（DCs）产生IL-23，激活ILC3s产生IL-17和IL-22。因此，我们的数据表明，HMGB1-TLR2/4-DCs-IL-23级联途径增强了ILC3s产生IL-17和IL-22的功能，并且这种信号通路可能在IBD的发展中起关键作用。
