MERTK signalling in monocytes/macrophages in patients with liver disease
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.
|type of project||fundamental research|
|status||ongoing - recruiting phase|
|start of project||2015|
|end of project||2019|
|project manager||PD Dr. Dr. Christine Bernsmeier|