Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl4-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role of IDO1 in the development of hepatic fibrosis and cirrhosis. Patients with hepatitis B virus-induced cirrhosis and healthy volunteers were enrolled. For animals, carbon tetrachloride (CCl4) was used to establish liver fibrosis in wild-type and IDO1 knockout mice. Additionally, an IDO1 inhibitor (1-methyl-D-tryptophan) was administered to WT fibrosis mice. Liver lesions were positively correlated with serum IDO1 levels in both the clinical subjects and hepatic fibrosis mice. A positive correlation between serum IDO1 levels and liver stiffness values was found in the cirrhosis patients. Notably, IDO1 knockout mice were protected from CCl4-induced liver fibrosis, as reflected by unchanged serum alanine transaminase and aspartate transaminase levels and lower collagen deposition, α-smooth muscle actin expression and apoptotic cell death rates. On the other hand, tryptophan 2,3-dioxygenase (TDO), another systemic tryptophan metabolism enzyme, exhibited a compensatory increase as a result of IDO1 deficiency. Moreover, hepatic interleukin-17a, a characteristic cytokine of T helper 17 (Th17) cells, and downstream cytokines’ mRNA levels showed lower expression in the IDO1–/– model mice. IDO1 appears to be a potential hallmark of liver lesions, and its deficiency protects mice from CCl4-induced fibrosis mediated by Th17 cells down-regulation and TDO compensation.

Hepatoprotective Effects of Standardized Extracts from an Ancient Italian Apple Variety (Mela Rosa dei Monti Sibillini) against Carbon Tetrachloride (CCl4)-Induced Hepatotoxicity in Rats

“…Our data revealed that pretreatment with APE could normalize the levels of these parameters. Some reports have shown that CCl 4 administration led to collagen deposition, destruction of cellular boundaries, central vein congestion and inflammation of liver tissue [11,25,26]. In this study, the histopathological examination of the liver indicated that CCl 4 intoxication caused disruption of cellular and lobular structures, inflammation and necrosis.…”

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

“…Among these processes, FZHY formula had been reported to cure liver fibrosis by positive regulation of macromolecule metabolic process ( Gao et al, 2016 ) and positive regulation of macromolecule biosynthetic process ( Liu et al, 2006 ; Cheng et al, 2013 ). In addition, cellular responses to endogenous stimulus ( Huang et al, 2016 ) and regulation of cell death ( Zhong et al, 2017 ) have been reported to be closely related to liver fibrosis, further experiments are needed to validate the interaction between FZHY formula and these two biological processes.…”

Tryptophan Metabolism via the Kynurenine Pathway: Implications for Graft Optimization during Machine Perfusion

“…Greater tryptophan metabolism during NMP is further significant as the liver oversees 90% of TRP catabolism via the KP, which generates both pro- and anti-inflammatory signaling metabolites [ 36 , 37 ]. Two rate-limiting enzymes catalyze the conversion of TRP to N-formylkynurenine in the first step of the KP: tryptophan 2, 3-dioxygenase (TDO) and indolamine-2,3-dioxygenase (IDO).…”