Corrigendum to: Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex

Immune-mediated hepatic injury plays a key role in the initiation and pathogenesis of diverse liver diseases. However, treatment choice for immune-mediated hepatic injury remains limited. Corilagin, a natural ellagitannin extracted from various traditional Chinese medicines, has been demonstrated to exhibit multiple pharmacological activities, such as anti-inflammatory, anti-tumor, and hepatoprotective properties. The present study aimed to investigate the effects of corilagin on immune-mediated hepatic injury using a murine model of concanavalin A (Con A)-induced hepatitis, which is well-characterized to study acute immune-mediated hepatitis. Herein, mice were administered corilagin (25 mg/kg) intraperitoneally twice at 12 h intervals, and 1 h later, the mice were challenged with Con A (20 mg/kg body weight); serum and liver samples were collected after 12 h. The results showed that corilagin significantly increased the survival of mice and reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. In addition, corilagin markedly improved histopathological damage, hepatocyte apoptosis, and oxidative stress in the liver. The activation of M1 macrophages in the hepatic mononuclear cells was also significantly reduced compared with that in the control group. The expression of M1 macrophage-associated proinflammatory cytokines and genes, including interleukin (IL)-6, IL-12, and inducible nitric oxide synthase (iNOS), was also decreased after corilagin treatment. Finally, the results demonstrated that corilagin regulated macrophage polarization by modulating the mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and interferon regulatory factor (IRF) signaling pathways. Thus, the findings indicate that corilagin protects mice from Con A-induced immune-mediated hepatic injury by limiting M1 macrophage activation via the MAPK, NF-κB, and IRF signaling pathways, suggesting corilagin as a possible treatment choice for immune-mediated hepatic injury.

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Deficiency of TGR5 Exacerbates Immune-Mediated Cholestatic Hepatic Injury by Stabilizing the β-Catenin Destruction Complex

SSRN Electronic Journal ◽

10.2139/ssrn.3234821 ◽

2018 ◽

Author(s):

Jianhua Rao ◽

Chao Yang ◽

Hao Lu ◽

Yuanchang Hu ◽

Shikun Yang ◽

...

Keyword(s):

Hepatic Injury ◽

Immune Mediated

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Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex

International Immunology ◽

10.1093/intimm/dxaa002 ◽

2020 ◽

Vol 32 (5) ◽

pp. 321-334 ◽

Cited By ~ 2

Author(s):

Jianhua Rao ◽

Chao Yang ◽

Shikun Yang ◽

Hao Lu ◽

Yuanchang Hu ◽

...

Keyword(s):

Energy Homeostasis ◽

Hepatic Injury ◽

Inflammatory Responses ◽

Therapeutic Implications ◽

Immune Mediated ◽

Duct Ligation ◽

G Protein Coupled ◽

Therapeutic Perspective

Abstract Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5−/−) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5−/− bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5−/− macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5−/− BMDMs. Notably, expression of β-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3β to repress the interaction between Gsk3β and β-catenin, thus disrupting the β-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated β-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5−/− BMDMs. From a therapeutic perspective, TGR5−/− BMDM administration aggravated BDL-induced CHI, which was effectively rescued by β-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the β-catenin destruction complex, with therapeutic implications for the management of human CHI.

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Diclofenac Synthesis

10.31219/osf.io/t39fx ◽

2021 ◽

Author(s):

Aymen Labidi

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Hepatic Injury ◽

Liver Toxicity ◽

Reactive Intermediates ◽

The United States ◽

Hepatocellular Injury ◽

Hepatocellular Damage ◽

Immune Mediated ◽

Inflammatory Drugs

Diclofenac is an NSAID, Non-Steroidal Anti-Inflammatory Drugs, widely used clinically in the treatement of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and has been available in the United States since 1988 (Banks et al. 1995). Diclofenac can cause hepatotoxicity, and despite the rare nature of these events, affects a large number of people due to its widespread usage. It is one of the most common drugs associated with idiosyncratic hepatic injury (Daly et al. 2007). From November 1988 to June 1991 the FDA received 180 cases of diclofenac-induced adverse hepatic injury of which 79% were female, 71% were elderly patients (above the age of 60), and 77% of the patients had osteoarthritis. In most of the cases the liver injury was characterized by hepatocellular damage or mixed hepatocellular injury, and there were some cases of cholestasis (Banks et al. 1995). The incidence of diclofenac hepatotoxicity has been reported to be 6.3 per 100 000 patients (DeAbajo et al. 2004). Bioactivation to reactive intermediates, their disposition, the production of oxidative stress, mitochondrial damage, and immune-mediated mechanisms have been suggested to play a role in diclofenac-mediated liver toxicity

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Allicin, the active component of garlic, prevents immune-mediated, concanavalin A-induced hepatic injury in mice.

Liver International ◽

10.1111/j.1478-3231.2005.01050.x ◽

2005 ◽

Vol 25 (3) ◽

pp. 613-621 ◽

Cited By ~ 39

Author(s):

Rafael Bruck ◽

Hussein Aeed ◽

Eli Brazovsky ◽

Talia Noor ◽

Rami Hershkoviz

Keyword(s):

Concanavalin A ◽

Active Component ◽

Hepatic Injury ◽

Immune Mediated

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mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1α-dependent glycolytic pathway

Journal of Leukocyte Biology ◽

10.1189/jlb.2a1115-492r ◽

2016 ◽

Vol 100 (6) ◽

pp. 1349-1362 ◽

Cited By ~ 11

Author(s):

Xi Chen ◽

Zhengguo Zhang ◽

Yujing Bi ◽

Zan Fu ◽

Pingsheng Gong ◽

...

Keyword(s):

Hepatic Injury ◽

Mtor Signaling ◽

Glycolytic Pathway ◽

Immune Mediated

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Overexpression of KLF14 protects against immune-mediated hepatic injury in mice

Laboratory Investigation ◽

10.1038/s41374-018-0134-4 ◽

2018 ◽

Vol 99 (1) ◽

pp. 37-47 ◽

Cited By ~ 2

Author(s):

Xiaoyan Chen ◽

Qinghai Tan ◽

Yunwu Wang ◽

Huijie Lv ◽

Zhihui Wang ◽

...

Keyword(s):

Hepatic Injury ◽

Immune Mediated

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24-Nor-Ursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation

10.1101/2021.01.09.426037 ◽

2021 ◽

Author(s):

Ci Zhu ◽

Nicole Boucheron ◽

André C. Müller ◽

Peter Májek ◽

Thierry Claudel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Liver Diseases ◽

Hepatic Injury ◽

Cell Function ◽

Cell Immune Response ◽

Immune Mediated ◽

Mtorc1 Signaling ◽

Lcmv Infection

AbstractBackground & Aims24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8+ T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects.MethodsNorUDCA effects on CD8+ T cell function in vivo were investigated in a hepatic injury model system induced by excessive CD8+ T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8+ T cells in vitro. Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8+ T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients.ResultsIn vivo NorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8+ T cells. With MS, we identified that NorUDCA regulates CD8+ T cells via targeting mTORC1. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating human CD8+ T cells.ConclusionsNorUDCA possesses a yet-unrecognized direct modulatory potency on CD8+ T cells and attenuates excessive CD8+ T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

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