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Inhibition of glutamine synthetase in monocytes from patients with Acute-on-Chronic Liver Failure resuscitates their antibacterial and inflammatory capacity

Tijdschriftbijdrage - Tijdschriftartikel

Objective Acute-on-chronic liver failure (ACLF) is associatedwith dysfunctional circulating monocytes whereby patientsbecome highly susceptible to bacterial infections. Here, weidentify the pathways underlying monocyte dysfunctionin ACLF and we investigate whether metabolic rewiringreinstates their phagocytic and inflammatory capacity.Design Following phenotypic characterisation, weperformed RNA sequencing on CD14+CD16− monocytesfrom patients with ACLF and decompensated alcoholiccirrhosis. Additionally, an in vitro model mimicking ACLFpatient-derived features was implemented to investigate theefficacy of metabolic regulators on monocyte function.Results Monocytes from patients with ACL F featuredelevated frequencies of interleukin (IL)-10-producingcells, reduced human leucocyte antigen DR isotype(HLA-DR) expression and impaired phagocytic andoxidative burst capacity. Transcriptional profiling ofisolated CD14+CD16− monocytes in ACLF revealedupregulation of an array of immunosuppressiveparameters and compromised antibacterial and antigenpresentation machinery. In contrast, monocytes indecompensated cirrhosis showed intact capacityto respond to inflammatory triggers. Culturinghealthy monocytes in ACLF plasma mimicked theimmunosuppressive characteristics observed in patients,inducing a blunted phagocytic response and metabolicprogram associated with a tolerant state. Metabolicrewiring of the cells using a pharmacological inhibitor ofglutamine synthetase, partially restored the phagocyticand inflammatory capacity of in vitro generated- aswell as ACLF patient-derived monocytes. Highlightingits biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytespositively correlated with disease severity scores.Conclusion In ACL F, monocytes feature a distincttranscriptional profile, polarised towards animmunotolerant state and altered metabolism. Wedemonstrated that metabolic rewiring of ACLF monocytespartially revives their function, opening up new optionsfor therapeutic targeting in these patients
Tijdschrift: Gut
ISSN: 0017-5749
Issue: 10
Volume: 68
Pagina's: 1872 - 1883
Aantal pagina's: 11
Jaar van publicatie:2019