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Cited by 228Inflammasome and immune disordersAlcohol Consumption and Health EffectsLiver Disease Diagnosis and Treatment

Pyroptosis by caspase11/4‐gasdermin‐D pathway in alcoholic hepatitis in mice and patients

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Khanova, Elena, Wu, Raymond, Wang, Wen, Yan, Rui, Chen, Yibu, French, Samuel W., Llorente, Cristina, Pan, Stephanie Q. +9 more·2018·Hepatology
DOI 10.1002/hep.29645PMC PMC5906140
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Abstract

Alcoholic hepatitis (AH) continues to be a disease with high mortality and no efficacious medical treatment. Although severe AH is presented as acute on chronic liver failure, what underlies this transition from chronic alcoholic steatohepatitis (ASH) to AH is largely unknown. To address this question, unbiased RNA sequencing and proteomic analyses were performed on livers of the recently developed AH mouse model, which exhibits the shift to AH from chronic ASH upon weekly alcohol binge, and these results are compared to gene expression profiling data from AH patients. This cross‐analysis has identified Casp11 ( CASP4 in humans) as a commonly up‐regulated gene known to be involved in the noncanonical inflammasome pathway. Immunoblotting confirms CASP11/4 activation in AH mice and patients, but not in chronic ASH mice and healthy human livers. Gasdermin‐D (GSDMD), which induces pyroptosis (lytic cell death caused by bacterial infection) downstream of CASP11/4 activation, is also activated in AH livers in mice and patients. CASP11 deficiency reduces GSDMD activation, bacterial load in the liver, and severity of AH in the mouse model. Conversely, the deficiency of interleukin‐18, the key antimicrobial cytokine, aggravates hepatic bacterial load, GSDMD activation, and AH. Furthermore, hepatocyte‐specific expression of constitutively active GSDMD worsens hepatocellular lytic death and polymorphonuclear leukocyte inflammation. Conclusion: These results implicate pyroptosis induced by the CASP11/4‐GSDMD pathway in the pathogenesis of AH. (H epatology 2018;67:1737‐1753).

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  • Hepatocytes begin to die by lytic forms of cell death including necroptosis, pyroptosis and ferroptosis, causing damage to surrounding tissue.

    “Hepatocytes begin to die by lytic forms of cell death including necroptosis(202, 203), pyroptosis(204, 205) and ferroptosis(206), causing damage to surrounding tissue.”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [205]

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Authors
Khanova, E., Wu, R., Wang, W., Yan, R., Chen, Y., French, S. W., Llorente, C., Pan, S. Q., Yang, Q., Li, Y., Lazaro, R., Ansong, C., Smith, R. D., Bataller, R., Morgan, T., Schnabl, B., & Tsukamoto, H.
Affiliations
  • University of Southern California (US)
  • Harbor–UCLA Medical Center (US)
  • University of California San Diego (US)
  • Pacific Northwest National Laboratory (US)
  • Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine,University of Pittsburgh,Pittsburgh,PA
  • VA Long Beach Healthcare System (US)
Corresponding author
Tsukamoto, Hidekazu
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-02-27
Volume
67
Issue
5
Pages
1737-1753
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.29645
PMC
PMC5906140
OpenAlex
W2767773677
Cited by
228
References
4
Citations by year
2026: 9 · 2025: 20 · 2024: 30 · 2023: 27 · 2022: 45 · 2021: 30 · 2020: 32 · 2019: 22 · 2018: 12 · 2017: 1
FWCI
7.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Energy (GM103493)
  • U.S. Department of Veterans Affairs (1I01BX00199)
  • Johns Hopkins University
  • USC Norris Comprehensive Cancer Center (P30CA014089)
  • National Institutes of Health (5p41gm103493-20, R01‐AA020703, P41-GM103493, GM103493)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA020703, U01AA021908, U01AA021886, U01AA018389, U01021898, U01AA021856, U01AA021884, R01AA018389, U01AA021898, R24AA012885, P50AA011999, R24AA025017)
  • National Cancer Institute (P30CA014089)
  • National Institute of General Medical Sciences (GM103493, P41-GM103493)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090794, P30DK048522)
  • Biological and Environmental Research
  • Pacific Northwest National Laboratory
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
alcoholic hepatitis, pyroptosis, caspase-11, caspase-4, gasdermin D, non-canonical inflammasome, IL-18, alcoholic steatohepatitis, acute-on-chronic liver failure
MeSH terms
Pyroptosis, Gasdermins, Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Hepatitis, Alcoholic, Humans, Liver, Male, Mice, Inbred C57BL, Neoplasm Proteins, Immunoblotting, Signal Transduction, Cytokines, Caspases, Gene Expression Profiling, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, Mice, Caspases, Initiator, Transcriptome, Real-Time Polymerase Chain Reaction

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