Related Experiment Video
Updated: Dec 26, 2025
Characterization of Human Monocyte-derived Dendritic Cells by Imaging Flow Cytometry: A Comparison between Two Monocyte Isolation Protocols
Published on: October 18, 2016
Epigenetic basis for monocyte dysfunction in patients with severe alcoholic hepatitis
Laura Weichselbaum1, Abdulkader Azouz2, Kinga K Smolen2
1Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, Belgium; Université Libre de Bruxelles, Laboratory of Experimental Gastroenterology, Brussels, Belgium.
Background & Aims:
Severe forms of alcohol-related liver disease are associated with increased susceptibility to infections which are associated with poor prognosis. The cellular and molecular mechanisms responsible for this altered host defense are incompletely understood.
Methods:
We performed whole blood phenotypic analysis and ex vivo stimulation with various pathogen-associated molecular patterns (PAMPs). We included 34 patients with alcohol-related cirrhosis (18 of whom had biopsy-proven severe alcoholic hepatitis [sAH]), 12 healthy controls and 11 patients with chronic alcohol consumption without significant liver disease. We also evaluated the transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles of CD14+ monocytes from a subset of patients.
Results:
Circulating monocytes and conventional dendritic cells (DCs) from patients with sAH displayed complex alterations characterized by increased expression of both activating and inhibitory surface markers and an impaired pro-inflammatory response upon stimulation with PAMPs representative of gram-negative bacteria (lipopolysaccharide, Pam3CSK4) or fungal pathogens (Zymosan). Their decreased ability to produce more than 1 cytokine (polyfunctionality) upon PAMP stimulation correlated with the risk of developing infection at 28 days or mortality at 90 days. The presence of acute-on-chronic liver failure in patients with sAH did not significantly modify the immune profile of monocytes and DCs. Moreover, CD14+ monocytes of patients with sAH displayed altered transcriptional and epigenomic profiles characterized by downregulation of key innate immune and metabolic pathways and upregulation of important immunomodulatory factors.
Conclusions:
In patients with sAH, the altered transcriptional program and functional properties of monocytes that contribute to patients' susceptibility to infection have strong epigenetic determinants.
Lay Summary:
Patients with severe alcoholic hepatitis are at increased risk of infections, which contribute to the poor prognosis associated with the disease. Herein, we show that epigenetic determinants underly the immune cell dysfunction and inappropriate responses to pathogens that are associated with severe alcoholic hepatitis.
Insights
Severe alcoholic hepatitis impairs immune cell function, increasing infection risk and poor prognosis. Epigenetic changes in monocytes drive this immune dysfunction and susceptibility to pathogens.
Area of Science:
- Immunology
- Hepatology
- Genomics
Background:
- Severe alcoholic hepatitis (sAH) increases susceptibility to infections, leading to poor outcomes.
- The underlying cellular and molecular mechanisms of impaired host defense in sAH are not fully understood.
Purpose of the Study:
- To investigate the immune cell dysfunction in patients with severe alcoholic hepatitis.
- To identify the molecular and epigenetic mechanisms contributing to increased infection susceptibility in sAH.
Main Methods:
- Phenotypic analysis and ex vivo stimulation of whole blood from sAH patients, healthy controls, and chronic alcohol consumers.
- Transcriptomic (RNA-seq) and epigenomic (ATAC-seq) profiling of CD14+ monocytes.
- Evaluation of monocyte and dendritic cell responses to pathogen-associated molecular patterns (PAMPs).
Main Results:
- Monocytes and dendritic cells in sAH patients showed altered expression of surface markers and impaired pro-inflammatory responses to PAMPs.
- Reduced cytokine polyfunctionality in sAH patients correlated with infection risk and mortality.
- CD14+ monocytes from sAH patients exhibited altered transcriptional and epigenomic profiles, with downregulated immune/metabolic pathways and upregulated immunomodulatory factors.
Conclusions:
- Altered monocyte transcriptional programs and functional properties in sAH are driven by epigenetic determinants.
- These epigenetic factors contribute to immune cell dysfunction and increased infection susceptibility in severe alcoholic hepatitis.
More Related Videos
08:37Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer
Published on: November 15, 2024
10:17An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
