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Deciphering the cellular and molecular mechanisms implicated in innate immune cell dysfunction in patients with alcohol- related cirrhosis

par Weichselbaum, Laura
Président du jury Le Moine, Alain
Promoteur Goriely, Stanislas
Co-Promoteur Gustot, Thierry
Publication Non publié, 2023-04-03

Thèse de doctorat

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Résumé :

Background & Aims: Severe forms of alcohol-related liver diseaseare associated with increased susceptibility to infectionswhich are associated with poor prognosis. The cellular and molecularmechanisms responsible for this altered host defense areincompletely understood.Methods: We performed whole blood phenotypic analysis andex vivo stimulation with various pathogen-associated molecularpatterns (PAMPs). We included 34 patients with alcohol-relatedcirrhosis (18 of whom had biopsy-proven severe alcoholic hepatitis[sAH]), 12 healthy controls and 11 patients with chronic alcoholconsumption without significant liver disease. We also evaluatedthe transcriptomic (RNA-seq) and chromatin accessibility (ATACseq)profiles of CD14+ monocytes from a subset of patients.Results: Circulating monocytes and conventional dendritic cells(DCs) from patients with sAH displayed complex alterationscharacterized by increased expression of both activating andinhibitory surface markers and an impaired pro-inflammatoryresponse upon stimulation with PAMPs representative of gramnegativebacteria (lipopolysaccharide, Pam3CSK4) or fungalpathogens (Zymosan). Their decreased ability to produce morethan 1 cytokine (polyfunctionality) upon PAMP stimulationcorrelated with the risk of developing infection at 28 days ormortality at 90 days. The presence of acute-on-chronic liverfailure in patients with sAH did not significantly modify theimmune profile of monocytes and DCs. Moreover, CD14+ monocytesof patients with sAH displayed altered transcriptional andepigenomic profiles characterized by downregulation of keyinnate immune and metabolic pathways and upregulation ofimportant immunomodulatory factors.Conclusions: In patients with sAH, the altered transcriptional programand functional properties of monocytes that contribute to patients'susceptibility to infection have strong epigenetic determinants.