Projects in detail
Activation of MERTK-signalling in monocytes/macrophages – a mechanism to explain susceptibility to infection in patients with cirrhosis and a future therapeutic target?
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. 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 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. We hypothesise that activation of the MERTK signalling pathway plays a pivotal role in suppression of monocyte/macrophage innate immune responses to microbial challenge in patients with cirrhosis, explains their susceptibility to infection and provides a novel immunotherapeutic target to reverse immuneparesis: We propose that (i) the innate immune response is progressively impaired with progression of cirrhosis from Child A to C in concert with the severity of portal hypertension, and that (ii) MERTK signalling is activated in parallel to progression of disease severity and innate immune dysfunction. The mechanism involves (iii) increasing bacterial translocation with progressive cirrhosis and portal hypertension, activation of toll-like receptor (TLR) signaling through bacterial products and (iv) increasing cytokine production from the progressively inflamed liver also serves to activate the MERTK signalling cascade. The primary aim of the project is to investigate innate immune suppression during the evolution of cirrhosis and following acute decompensation (AD) in parallel to the activation of MERTK signalling on circulatory monocytes and tissue macrophages of cirrhotic patients. The secondary aim is to decipher the molecular mechanism leading to MERTK activation as inhibitor of innate immune response, which will involve investigating the role of (a) gutderived bacterial products on monocytes in-vitro and (b) inflammation of the liver and inflammatory cytokine production and its effect on tissue macrophages and monocytes ex-vivo. The tertiary aim is to evaluate the eligibility of MERTK inhibitors as future immunotherapeutic agents to prevent infectious complications.