The role of TAM receptors in immuneparesis in tissue compartments in liver failure syndromes

Abstract

Background: Decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF) – liver failure syndromes - are associated with increased incidence of bacterial infection, often spontaneous bacterial peritonitis (SBP), and a subsequent higher mortality. Within a model of pathological bacterial translocation, immuneparesis increases the susceptibility to infection. TAM receptor MerTK, expressed on monocytes and macrophages, mediates apoptotic cell clearance and attenuates responses to microbial challenge. Whilst MerTK+ circulating monocytes are expanded in ACLF, its role in conjunction with other TAM receptors, Axl and Tyro3, is not known in tissue compartments, such as the peritoneum and liver. In this thesis, I describe the tissue compartmental macrophage phenotype and function in cirrhosis and ACLF, focusing on TAM receptors, and the relationship to microenvironmental mediators. Methods: Combinations of flow cytometry, gene expression analyses and live cell imaging determined the phenotypic, functional and transcriptomic profile of MerTK+ monocytes/macrophages in cirrhosis and ACLF, in the circulation, peritoneum and liver. The composition of the ascitic microenviroment was determined by enzyme-linked immunosorbent assay (ELISA) and 1H-NMR metabonomics. Results: Circulating monocyte MerTK expression in ACLF was markedly elevated whilst Axl was low-level and Tyro3 variable. The peritoneum in cirrhosis was immunotolerant, characterized by MerTK[high] Axl[low] macrophages primed for apoptotic cell clearance, with impaired antimicrobial cytokine and oxidative burst responses but preserved phagocytosis. In ACLF, ascites contained pro-inflammatory cytokines, metabolites from anaerobic and lipid metabolism and increased apoptotic/necrotic cell death markers in conjunction with higher TAM receptor expression. Hepatic macrophages displayed intermediate MerTK expression. Conclusions: The work presented in this thesis has determined the TAM receptor expression across tissue compartments, the ascitic microenvironment in cirrhosis and ACLF and identified MerTK as a promising immunotherapeutic target to restore innate immune function in the evolution of ACLF.Open Acces