Zeng, Deng, Zhong, Gao, Ma, Mo, Li, Huang, Zhou, Lai, Xie, Xie, Chen, He, Lv, Gao (2020) Indoleamine 2, 3-dioxygenase 1enhanceshepatocytes ferroptosis in acute immune hepatitis associated with excess nitrative stress Free radical biology & medicine ()
Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, the molecular mechanisms of ferroptosis in acute immune hepatitis (AIH) are largely unknown. In this study, we investigated the classical ferroptotic events in the livers of mice with concanavalin A (ConA) to induce AIH. The dramatically upregulated gene indoleamine 2, 3-dioxygenase 1 (IDO1) was identified with AIH, and its role in generation of ferroptosis and reactive nitrogen species (RNS) was assessed both in vitro and in vivo by genetic deletion or pharmacologic inhibition of IDO1. We observed that ferroptosis contributed to the ConA-induced hepatic damage, which was confirmed by the therapeutical effects of ferroptosis inhibitor (ferrostatin-1). Noteworthy, upregulation of hepatic IDO1 and nitrative stress in ConA-induced hepatic damage were also remarkably inhibited by the ferroptosis abolishment. Additionally, IDO1 deficiency contributed to ferroptosis resistance by activating solute carrier family 7 member 11 (SLC7A11; also known as xCT) expression, accompanied with the reductions of murine liver lesions and RNS. Meanwhile, IDO inhibitor 1-methyl tryptophan alleviated murine liver damage with the reduction of inducible nitric oxide synthase and 3-nitrotyrosine expression. Consistent with the results in vivo, hepatocytes-specific knockdown of IDO1 led to ferroptosis resistance upon exposure to ferroptosis-inducing compound (Erastin) in vitro, whereas IDO1 overexpression aggravated the classical ferroptotic events, and the RNS stress. Overall, these results revealed a novel molecular mechanism of ferroptosis with the key feature of nitrative stress in ConA-induced liver injury, and also identified IDO1-dependent ferroptosis as a potential target for the treatment of AIH. Copyright © 2020 Elsevier Inc. All rights reserved.