RT Journal Article
SR Electronic
T1 Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2018-316888
DO 10.1136/gutjnl-2018-316888
A1 Hannelie Korf
A1 Johannie du Plessis
A1 Jos van Pelt
A1 Sofie De Groote
A1 David Cassiman
A1 Len Verbeke
A1 Bart Ghesquière
A1 Sarah-Maria Fendt
A1 Matthew J Bird
A1 Ali Talebi
A1 Matthias Van Haele
A1 Rita Feio-Azevedo
A1 Lore Meelberghs
A1 Tania Roskams
A1 Rajeshwar P Mookerjee
A1 Gautam Mehta
A1 Rajiv Jalan
A1 Thierry Gustot
A1 Wim Laleman
A1 Frederik Nevens
A1 Schalk Willem van der Merwe
YR 2018
UL http://gut.bmj.com/content/early/2018/12/21/gutjnl-2018-316888.abstract
AB Objective Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.Design Following phenotypic characterisation, we performed RNA sequencing on CD14+CD16− monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.Results Monocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16− monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.Conclusion In ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.