Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2.
Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2.
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表观遗传药物筛选发现 IOX1 通过靶向 TET2 为 Th17 介导的炎症抑制剂
DOI：
10.1016/j.ebiom.2022.104333
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发表时间：
2022-12
期刊：
影响因子：
11.1
通讯作者：
Wei, Lai
中科院分区：
文献类型：
--
作者：
Hu, Xiao;Zou, Yanli;Copland, David A.;Schewitz-Bowers, Lauren P.;Li, Yan;Lait, Philippa J. P.;Stimpson, Madeleine;Zhang, Zhihui;Guo, Shixin;Liang, Juanran;Chen, Tingting;Li, Jing Jing;Yuan, Sujing;Li, Shuo;Zhou, Penghui;Liu, Yizhi;Dick, Andrew D.;Wen, Xiaofeng;Lee, Richard W. J.;Wei, Lai
靶向辅助性T细胞，特别是Th17+细胞，已经成为许多自身免疫性疾病的一种可行的治疗方法。利用体外培养系统，我们筛选了小鼠Th1和Th17细胞中干扰素-γ和IL-17表达抑制物的表观遗传学化合物文库。这证明IOX1是一种有效的抑制IL-17在小鼠和人的CD4+T细胞中的表达。此外，我们发现IOX1通过靶向其启动子上的TET2活性而直接抑制Th17细胞中IL17A的表达。使用已建立的眼内炎症临床前模型，IOX1在体内治疗减少了Th17+细胞向炎症和组织损伤部位的迁移/渗透。这些结果提供了IOX1作为一种可行的炎症性疾病治疗方法的强大潜力的证据，特别是在眼睛方面。本研究得到了国家重点研究发展计划项目中国2021YFA1101200(2021YFA1101204)TO LW和XW；国家自然科学基金中国81900844~XH和82171041 TLW；中国博士后科学基金2021M700776和广东省中医药管理局科研项目20221373~YZ；国家卫生研究院莫尔菲兹眼科医院生物医学研究中心NHS基金会信托基金和英国伦敦大学眼科研究所(DAC、LPS、PJPL、MS、ADD和RWJL)的支持。所表达的观点是作者的观点，不一定是NIHR或英国卫生和社会保健部的观点。
Targeting helper T cells, especially Th17 cells, has become a plausible therapy for many autoimmune diseases. Using an in vitro culture system, we screened an epigenetics compound library for inhibitors of IFN-γ and IL-17 expression in murine Th1 and Th17 cultures. This identified IOX1 as an effective suppressor of IL-17 expression in both murine and human CD4+ T cells. Furthermore, we found that IOX1 suppresses Il17a expression directly by targeting TET2 activity on its promoter in Th17 cells. Using established pre-clinical models of intraocular inflammation, treatment with IOX1 in vivo reduced the migration/infiltration of Th17 cells into the site of inflammation and tissue damage. These results provide evidence of the strong potential for IOX1 as a viable therapy for inflammatory diseases, in particular of the eye. This study was supported by the National Key Research and Development Program of China 2021YFA1101200 (2021YFA1101204) to LW and XW; the National Natural Science Foundation of China 81900844 to XH and 82171041 to LW; the China Postdoctoral Science Foundation 2021M700776 and the Scientific Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine 20221373 to YZ; and the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS (National Health Service) Foundation Trust and University College London Institute of Ophthalmology, UK (DAC, LPS, PJPL, MS, ADD and RWJL). The views expressed are those of the authors and not necessarily those of the NIHR or the UK's Department of Health and Social Care.
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影响因子：
3.7
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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