Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2Research in context
Xiao Hu,
Yanli Zou,
David A. Copland,
Lauren P. Schewitz-Bowers,
Yan Li,
Philippa J.P. Lait,
Madeleine Stimpson,
Zhihui Zhang,
Shixin Guo,
Juanran Liang,
Tingting Chen,
Jing Jing Li,
Sujing Yuan,
Shuo Li,
Penghui Zhou,
Yizhi Liu,
Andrew D. Dick,
Xiaofeng Wen,
Richard W.J. Lee,
Lai Wei
Affiliations
Xiao Hu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Translational Health Sciences, University of Bristol, Bristol, UK
Yanli Zou
Experimental Research Center, Foshan Hospital Affiliated to Southern Medical University, Foshan, China
David A. Copland
Translational Health Sciences, University of Bristol, Bristol, UK
Lauren P. Schewitz-Bowers
Translational Health Sciences, University of Bristol, Bristol, UK
Yan Li
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Philippa J.P. Lait
Translational Health Sciences, University of Bristol, Bristol, UK
Madeleine Stimpson
Translational Health Sciences, University of Bristol, Bristol, UK
Zhihui Zhang
Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin 300384, China
Shixin Guo
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Juanran Liang
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Tingting Chen
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Jing Jing Li
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Sujing Yuan
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Shuo Li
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Penghui Zhou
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Yizhi Liu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Andrew D. Dick
Translational Health Sciences, University of Bristol, Bristol, UK; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, London, UK; UCL Institute of Ophthalmology, London, UK; University Hospitals Bristol NHS Foundation Trust, Bristol, UK
Xiaofeng Wen
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; MingMed Biotechnology, Guangzhou, China; Corresponding author.
Richard W.J. Lee
Translational Health Sciences, University of Bristol, Bristol, UK; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, London, UK; UCL Institute of Ophthalmology, London, UK; University Hospitals Bristol NHS Foundation Trust, Bristol, UK; Corresponding author.
Lai Wei
MingMed Biotechnology, Guangzhou, China; Schoole of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; Corresponding author.
Summary: Background: Targeting helper T cells, especially Th17 cells, has become a plausible therapy for many autoimmune diseases. Methods: 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. Findings: 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. Interpretation: These results provide evidence of the strong potential for IOX1 as a viable therapy for inflammatory diseases, in particular of the eye. Funding: 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.
