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Abstract
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.
- acute liver failure
- alcoholic liver disease
- immunology in hepatology
- macrophages
- bacterial infection
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Footnotes
Contributors SvdM, HK and JvP conceptualised and planned the study. HK, JdP and SvdM wrote the protocol. HK and JdP performed the flow cytometry, monocyte functional studies, gene expression and multiplex cytokine assays. AT, RFA and SDG assisted with the Incucyte experiments. LM documented the clinical patient information. MVH and TR performed immunohistochemistry experiments. BG, DC, MB and S-MF provided support for the metabolic aspects of the study. JvP performed the RNA sequence pathway identification, the hierarchic clustering and statistical analysis. RJ, GM, RPM, TG, DC, FN, WL, LV and SvdM recruited and cared for the patients. HK and SvdM wrote the manuscript.
Funding This work was supported by internal funding from the UZ Leuven (KOOR) and KU Leuven (C1) as well as by the FWO and Gilead Sciences.
Competing interests SvdM, FN and DC are recipients of Flanders fund for scientific research (FWO fundamenteel-klinisch mandaat). RJ has research collaborations with Yaqrit and Takeda. RJ is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt. He is also the founder of a UCL spin out, Yaqrit Limited, Ammun Limited and Cyberliver Limited.
Ethics approval Medical Ethics Committee (KU Leuven/UZ Leuven; S54588).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The RNA sequencing data will become available at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE93265.
Patient consent for publication Not required.