Host Mechanisms in Viral Hepatitis

Lang, Karl S.

doi:10.1159/000282061

Cited by 4 publications

(4 citation statements)

References 193 publications

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“…Viral hepatitis and alcohol abuse are the two major causes of chronic liver disease worldwide, and both factors frequently coexist and synergistically promote liver disease progression;1-4 however, the underlying mechanisms remain obscure. In viral hepatitis, activation of T cells plays an important role in eliminating viruses and promotes hepatocellular damage 5, 6. Injection of concanavalin A (ConA), a T-cell mitogen, has been widely used to study how T-cell activation induces liver injury in mice 7-9.…”

Section: Introductionmentioning

confidence: 99%

Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids

Gao¹,

Zhou

Ren³

et al. 2018

Gut

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Section: Introductionmentioning

confidence: 99%

Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids

Gao¹,

Zhou

Ren³

et al. 2018

Gut

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“…Infection with a high inoculum (10 6 FFU) of LCMV-WE causes acute hepatitis [15], [16]; the virus is usually cleared by wild-type mice within about two weeks. LCMV hepatitis is a useful model for human hepatitis virus infections, in so far as LCMV-WE, similar to human hepatitis viruses, causes a non-cytopathic infection, in which the liver damage is mediated almost entirely by the antiviral immune response [16]. Also in LCMV infection, CD8+ T cells are essential for the elimination of the virus [17], [18].…”

Section: Introductionmentioning

confidence: 99%

CD4+ T-Cell Help Is Required for Effective CD8+ T Cell-Mediated Resolution of Acute Viral Hepatitis in Mice

et al. 2014

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Cytotoxic CD8+ T cells are essential for the control of viral liver infections, such as those caused by HBV or HCV. It is not entirely clear whether CD4+ T-cell help is necessary for establishing anti-viral CD8+ T cell responses that successfully control liver infection. To address the role of CD4+ T cells in acute viral hepatitis, we infected mice with Lymphocytic Choriomeningitis Virus (LCMV) of the strain WE; LCMV-WE causes acute hepatitis in mice and is cleared from the liver by CD8+ T cells within about two weeks. The role of CD4+ T-cell help was studied in CD4+ T cell-lymphopenic mice, which were either induced by genetic deficiency of the major histocompatibility (MHC) class II transactivator (CIITA) in CIITA−/− mice, or by antibody-mediated CD4+ cell depletion. We found that CD4+ T cell-lymphopenic mice developed protracted viral liver infection, which seemed to be a consequence of reduced virus-specific CD8+ T-cell numbers in the liver. Moreover, the anti-viral effector functions of the liver-infiltrating CD8+ T cells in response to stimulation with LCMV peptide, notably the IFN-γ production and degranulation capacity were impaired in CIITA−/− mice. The impaired CD8+ T-cell function in CIITA−/− mice was not associated with increased expression of the exhaustion marker PD-1. Our findings indicate that CD4+ T-cell help is required to establish an effective antiviral CD8+ T-cell response in the liver during acute viral infection. Insufficient virus control and protracted viral hepatitis may be consequences of impaired initial CD4+ T-cell help.

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“…Immune-mediated hepatitis occurs when the liver is attacked by the body's immune system causing inflammation and ultimately cirrhosis, as well as when virus-specific T cells destroy infected hepatocytes in viral hepatitis [3]. In autoimmune hepatitis (AIH), T cells control the progression of the disease by interacting with other immune cells including B cells, dendritic cells (DCs), macrophages, and natural killer (NK) cells [4,5]. Intravenous injection of concanavalin A (ConA) into mice has been widely used to establish a mouse model of fulminant immunological liver injury in vivo [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells

Zhuang¹,

Liu²,

Li³

et al. 2023

Int. J. Biol. Sci.

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Increasing evidence suggests that immunometabolism has started to unveil the role of metabolism in shaping immune function and autoimmune diseases. In this study, our data show that purinergic receptor P2Y12 (P2RY12) is highly expressed in concanavalin A (ConA)-induced immune hepatitis mouse model and serves as a potential metabolic regulator in promoting metabolic reprogramming from oxidative phosphorylation to glycolysis in T cells. P2RY12 deficiency or inhibition of P2RY12 with P2RY12 inhibitors (clopidogrel and ticagrelor) are proved to reduce the expression of inflammatory mediators, cause CD4 + and CD8 + effector T cells hypofunction and protect the ConA-induced immune hepatitis. A combined proteomics and metabolomics analysis revealed that P2RY12 deficiency causes redox imbalance and leads to reduced aerobic glycolysis by downregulating the expression of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway, indicating that HK2 might be a promising candidate for the treatment of diseases associated with T cell activation. Further analysis showed that P2RY12 prevents HK2 degradation by activating the PI3K/Akt pathway and inhibiting lysosomal degradation. Our findings highlight the importance of the function of P2RY12 for HK2 stability and metabolism in the regulation of T cell activation and suggest that P2RY12 might be a pivotal regulator of T cell metabolism in ConA-induced immune hepatitis.

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Host Mechanisms in Viral Hepatitis

Cited by 4 publications

References 193 publications

Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids

Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids

CD4+ T-Cell Help Is Required for Effective CD8+ T Cell-Mediated Resolution of Acute Viral Hepatitis in Mice

Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells

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