An insight into the mechanism and molecular basis of dysfunctional immune response involved in cholestasis

Zou, Mengzhi; Wang, Aizhen; Wei, Jiajie; Cai, Heng; Yu, Zixun; Zhang, Luyong; Wang, Xinzhi

doi:10.1016/j.intimp.2020.107328

Cited by 14 publications

(8 citation statements)

References 127 publications

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“…BA can act as a signaling molecule that induces the release of chemokines to recruit inflammatory cells . Compared to the control group, the mRNA expression of Cxcl9 was increased after triptolide administration, and its expression was decreased in CXCR3-deficient mice after triptolide administration (Figure A).…”

Section: Resultsmentioning

confidence: 98%

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Mei,

Li,

et al. 2023

Chem. Res. Toxicol.

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The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alphanaphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT-and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17 + CD4 + T cells, IFN-γ/IL-4/IL-17 + iNKT cells and IFN-γ/IL-4 + NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT-and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ + NK cells and IL-4 + NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4 + iNKT cells and IL-17 + iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT-and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.

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Section: Resultsmentioning

confidence: 98%

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Mei,

Li,

et al. 2023

Chem. Res. Toxicol.

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“…This, in combination with disturbed hepatic bile acid synthesis [37], results in an altered bile acid composition and localization and hence to disturbed bile acid signaling during cholestasis. Evidently, bile acids influence the immune system during cholestasis and thereby affect disease progression through various complex pathways [38,39]. This paragraph will elaborate on bile acid actions on immunity during cholestasis and on potential treatment options that target bile acid metabolism.…”

Section: Bile Acids In Cholestatic Liver Diseasesmentioning

confidence: 99%

Role of bile acids in inflammatory liver diseases

et al. 2021

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Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

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“…Nevertheless, the intrahepatic accumulation of bile acids at supraphysiological levels constitutes a major Ivyspring International Publisher cause of toxic injury in liver parenchyma [3][4][5], which may progress to biliary fibrosis associated or not with cirrhosis, and eventually, to end-stage liver disease. Similarly to other CLDs, an inflammatory response plays an important role in cholestatic disorders [6][7][8]. In this sense, regardless of their intrinsic toxicity, bile acids have emerged as signaling molecules participating in this inflammatory response, been able to stimulate secretion of cytokines and chemokines in hepatocytes and cholangiocytes, possibly contributing to the inflammatory misregulation and disease progression [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury

García-Sáez,

Figueroa-Fuentes,

González-Corralejo

et al. 2024

Int. J. Biol. Sci.

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Chronic cholestatic damage is associated to both accumulation of cytotoxic levels of bile acids and expansion of adult hepatic progenitor cells (HPC) as part of the ductular reaction contributing to the regenerative response. Here, we report a bile acid-specific cytotoxic response in mouse HPC, which is partially impaired by EGF signaling. Additionally, we show that EGF synergizes with bile acids to trigger inflammatory signaling and NLRP3 inflammasome activation in HPC. Aiming at understanding the impact of this HPC specific response on the liver microenvironment we run a proteomic analysis of HPC secretome. Data show an enrichment in immune and TGF-β regulators, ECM components and remodeling proteins in HPC secretome. Consistently, HPC-derived conditioned medium promotes hepatic stellate cell (HSC) activation and macrophage M1-like polarization. Strikingly, EGF and bile acids co-treatment leads to profound changes in the secretome composition, illustrated by an abolishment of HSC activating effect and by promoting macrophage M2-like polarization. Collectively, we provide new specific mechanisms behind HPC regulatory action during cholestatic liver injury, with an active role in cellular interactome and inflammatory response regulation. Moreover, findings prove a key contribution for EGFR signaling jointly with bile acids in HPC-mediated actions.

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An insight into the mechanism and molecular basis of dysfunctional immune response involved in cholestasis

Cited by 14 publications

References 127 publications

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

Role of bile acids in inflammatory liver diseases

Uncovering a Novel Functional Interaction Between Adult Hepatic Progenitor Cells, Inflammation and EGFR Signaling During Bile Acids-Induced Injury

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