ArticleJournal of hepatology2016
Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles.
Article in Journal of hepatology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 152 papers.
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Who cites it
152 citing papers in PubMed, 219 citations in OpenAlex.
- Emricasan (IDN-6556) Lowers Portal Pressure in Patients With Compensated Cirrhosis and Severe Portal Hypertension.Hepatology (Baltimore, Md.) · 2019Trial
- Predictive value of serum CCL18 for recurrence and invasiveness in pituitary neuroendocrine tumors.Journal of endocrinological investigation · 2026Article
- Novel perspectives on extracellular vesicles in autoimmune diseases: immunogenicity, inflammation, and immune surveillance.The Journal of clinical investigation · 2026Review
- Hepatocyte-hepatic stellate cell interactions in liver fibrosis: Mechanisms and therapeutic implications.Hepatology communications · 2026Review
- Interferon Regulatory Factors in Alcohol-Associated Liver Disease: Cell-Type Programs, Danger Signaling, and Therapeutic Opportunities.Current issues in molecular biology · 2026Review
- Hepatitis B virus, alcohol, and liver cancer.Frontiers in oncology · 2026Review
- Unraveling the Interplay Between Alcohol, Immunity, and Gastric Cancer: A Genomic Approach.Food science & nutrition · 2025Article
- Mitigating alcohol-induced liver oxidative stress and dysregulated autophagy with protein hydrolysates derived from rainbow trout by-products.Biochemistry and biophysics reports · 2025Article
- Circulating extracellular vesicles predict outcome in patient undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement.Scientific reports · 2025Article
- Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease.Cellular & molecular immunology · 2025Review
- Extracellular vesicles for targeted drug delivery: advances in surface modification strategies and therapeutic applications.Journal of translational medicine · 2025Review
- Physicochemical Modulation Strategies for Mass Production of Extracellular Vesicle.Tissue engineering and regenerative medicine · 2025Review
- Extracellular Vesicles as Biomarkers in Chronic Hepatobiliary Diseases: An Overview of Their Interplay.International journal of molecular sciences · 2025Review
- The role of gut microbiota, exosomes, and their interaction in the pathogenesis of ALD.Journal of advanced research · 2025Review
- MicroRNA Expression Profile in the Patient's Plasma Exosomes of Alcohol-Induced Osteonecrosis of Femoral Head: Potential Vascular Regulation Mechanism.Journal of cellular and molecular medicine · 2025Article
- Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis.Biomedicines · 2025Article
- Multidimensional insights into exosomes in hepatocellular carcinoma: from genesis to clinical application.Frontiers in immunology · 2025Review
- Emerging role of exosomes during the pathogenesis of viral hepatitis, non-alcoholic steatohepatitis and alcoholic hepatitis.Human cell · 2024Review
- Extracellular vesicle miR-206 improves chronic binge alcohol-mediated decreased myoblast differentiation in SIV-infected female macaques.American journal of physiology. Cell physiology · 2024Article
- Extracellular Vesicles in Viral Liver Diseases.Viruses · 2024Review
92 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsThe mechanisms by which hepatocyte exposure to alcohol activates inflammatory cells such as macrophages in alcoholic liver disease (ALD) are unclear. The role of released nano-sized membrane vesicles, termed extracellular vesicles (EV), in cell-to-cell communication has become increasingly recognized. We tested the hypothesis that hepatocytes exposed to alcohol may increase EV release to elicit macrophage activation.
methodsPrimary hepatocytes or HepG2 hepatocyte cell lines overexpressing ethanol-metabolizing enzymes alcohol dehydrogenase (HepG2(ADH)) or cytochrome P450 2E1 (HepG2(Cyp2E1)) were treated with ethanol and EV release was quantified with nanoparticle tracking analysis. EV mediated macrophage activation was monitored by analysing inflammatory cytokines and macrophage associated mRNA expression, immunohistochemistry, biochemical serum alanine aminotransferase and triglycerides analysis in our in vitro macrophage activation and in vivo murine ethanol feeding studies.
resultsEthanol significantly increased EV release by 3.3-fold from HepG2(Cyp2E1) cells and was associated with activation of caspase-3. Blockade of caspase activation with pharmacological or genetic approaches abrogated alcohol-induced EV release. EV stimulated macrophage activation and inflammatory cytokine induction. An unbiased microarray-based approach and antibody neutralization experiments demonstrated a critical role of CD40 ligand (CD40L) in EV mediated macrophage activation. In vivo, wild-type mice receiving a pan-caspase, Rho kinase inhibitor or with genetic deletion of CD40 (CD40(-/-)) or the caspase-activating TRAIL receptor (TR(-/-)), were protected from alcohol-induced injury and associated macrophage infiltration. Moreover, serum from patients with alcoholic hepatitis showed increased levels of CD40L enriched EV.
conclusionIn conclusion, hepatocytes release CD40L containing EV in a caspase-dependent manner in response to alcohol exposure which promotes macrophage activation, contributing to inflammation in ALD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.