Art

Reichweite

Bereiche

Status

Start

Ende

Finanzierungsart

Kurzbeschreibung/Zielsetzung

Cirrhosis of the liver is a condition with a high mortality and raising prevalence worldwide. Infectious complications are highly frequent and independent predictors of outcome in patients with cirrhosis – being the leading cause of decompensation, ‘acute-on-chronic’ liver failure (ACLF) and death. There is no treatment option other than transplantation, applicable at early stages and to only a minority of patients. Susceptibility to infection has been documented in patients with cirrhosis and has been attributed to immuneparesis and monocyte dysfunction in the state of decompensation and liver failure. The underlying mechanisms are incompletely understood. Development of targeted immunomodulatory strategies might effectively reduce infectious complications and mortality in cirrhosis.
MER receptor tyrosine kinase (MERTK), expressed on monocytes/macrophages, plays a pivotal role in dampening innate immune responses. We have recently discovered and documented the role of MERTK in innate immune dysfunction in patients with ACLF. In ACLF monocytes/macrophages expressing MERTK are expanded in various compartments (the circulation, liver, extrahepatic tissues) where they dampen responses to microbial challenge. MERTK inhibitors have been developed and shown to improve innate immune responses of monocytes/macrophages in conditions such as lung injury and leucocyte anti-tumour response.
Recent data reveals that an acute decompensative episode triggers the expression of the MERTK on the surface of circulating monocytes/macrophages that may account for the observed immuneparesis and high susceptibility to infectious complications encountered in these patient cohorts. Dampening of innate immune response was already observed in patients with advanced cirrhosis (Child B/C) prior to AD, in whom monocyte expression of MERTK was not significantly elevated, suggesting that activation of MERTK signalling pathway may precede its receptor up-regulation. In line with this theory, MERTK ligands, e.g. Gas6, a protein produced predominantly in endothelial cells, are significantly elevated in cirrhotic patients compared to controls. The mechanisms of as to how MERTK signalling becomes activated in the progression from compensated to decompensated cirrhosis and impacts on response to microbial challenge are however unexplored. Understanding the mechanism that underpins this pathophysiological process might enable development of a future targeted immunotherapy for patients with cirrhosis and offset infectious complications.