Laura Weichselbaum1, Abdulkader Azouz2, Kinga K Smolen2, Jishnu Das3, Marion Splittgerber2, Antonia Lepida4, Christophe Moreno5, Jonas Schreiber4, Thomas Sersté6, Eric Trepo5, Frederick Libert7, Thierry Gustot8, Stanislas Goriely9. 1. Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, Belgium; Université Libre de Bruxelles, Laboratory of Experimental Gastroenterology, Brussels, Belgium. 2. Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, Belgium. 3. Ragon Institute of MGH, MIT and Harvard; Department of Biological Engineering, MIT; Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine. 4. Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Brussels, Belgium. 5. Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Brussels, Belgium; Université Libre de Bruxelles, Laboratory of Experimental Gastroenterology, Brussels, Belgium. 6. Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Brussels, Belgium; Department of Hepato-gastroenterology, C.U.B. Saint Pierre, Brussels, Belgium. 7. Université Libre de Bruxelles, BRIGHTcore ULB-VUB and Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM), Brussels, Belgium. 8. Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Brussels, Belgium; Université Libre de Bruxelles, Laboratory of Experimental Gastroenterology, Brussels, Belgium; Inserm Unité 1149, Centre de Recherche sur l'inflammation (CRI), Paris, France. Electronic address: thierry.gustot@erasme.ulb.ac.be. 9. Université Libre de Bruxelles, Institute for Medical Immunology (IMI), Gosselies, Belgium. Electronic address: stgoriel@ulb.ac.be.
Abstract
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.
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.
Authors: Emmanuel Weiss; Pierre de la Grange; Mylène Defaye; Juan José Lozano; Ferrán Aguilar; Pushpa Hegde; Ariane Jolly; Lucile Moga; Sukriti Sukriti; Banwari Agarwal; Haqeeqat Gurm; Marion Tanguy; Johanne Poisson; Joan Clària; Paer-Selim Abback; Axel Périanin; Gautam Mehta; Rajiv Jalan; Claire Francoz; Pierre-Emmanuel Rautou; Sophie Lotersztajn; Vicente Arroyo; François Durand; Richard Moreau Journal: Front Immunol Date: 2021-02-05 Impact factor: 7.561