MutT Homolog 1 Inhibitor Karonudib Attenuates Autoimmune Hepatitis by Inhibiting DNA Repair in Activated T Cells.

Abstract

Autoimmune hepatitis (AIH) is an inflammatory liver disease driven by the hyperactivation of various intrahepatic antigen-specific T cells due to a breach of immune tolerance. Studies in immunometabolism demonstrate that activated T cells harbor increased levels of reactive oxygen species that cause oxidative DNA damage. In this study, we assessed the potential of DNA damage repair enzyme MutT homolog 1 (MTH1) as a therapeutic target in AIH and karonudib as a novel drug for patients with AIH. We report herein that MTH1 expression was significantly increased in liver samples from patients with AIH compared to patients with chronic hepatitis B and nonalcoholic fatty liver disease and from healthy controls. In addition, the expression of MTH1 was positively correlated with AIH disease severity. We further found abundant T cells that expressed MTH1 in AIH. Next, we found that karonudib significantly altered T-cell receptor signaling in human T cells and robustly inhibited proliferation of human T cells in vitro. Interestingly, our data reflected a preferential inhibition of DNA damage repair in activated T cells by karonudib. Moreover, MTH1 was required to develop liver inflammation and damage because specific deletion of MTH1 in T cells ameliorated liver injury in the concanavalin A (Con A)-induced hepatitis model by inhibiting T-cell activation and proliferation. Lastly, we validated the protective effect of karonudib on the Con A-induced hepatitis model. Conclusion: MTH1 functions as a critical regulator in the development of AIH, and its inhibition in activated T cells reduces liver inflammation and damage.

• Authors: Yong Chen, Xiangwei Hua, Bingyuan Huang, Stella Karsten, Zhengrui You, Bo Li, You Li, Yikang Li, Jubo Liang, Jun Zhang, Yiran Wei, Ruiling Chen, Zhuwan Lyu, Xiao Xiao, Min Lian, Jue Wei, Jingyuan Fang, Qi Miao, Qixia Wang, Ulrika Warpman Berglung, Ruqi Tang, Thomas Helleday, Xiong Ma
• Journal: Hepatology communications (Hepatol Commun) Vol. 6 Issue 5 Pg. 1016-1031 (05 2022) ISSN: 2471-254X [Electronic] United States
• PMID: 34894107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Pyrimidines
• karonudib
• Concanavalin A
• Phosphoric Monoester Hydrolases

Topics

• Concanavalin A (pharmacology)
• DNA Damage
• DNA Repair
• Hepatitis, Autoimmune (drug therapy)
• Humans
• Inflammation (chemically induced)
• Phosphoric Monoester Hydrolases
• Pyrimidines
• T-Lymphocytes (metabolism)