Cirrhosis; Infection susceptibility; MERTK signalling; Monocytes/macrophages; Innate immune response; Liver
Brenig Robert, Pop Oltin T, Triantafyllou Evangelos, Geng Anne, Singanayagam Arjuna, Perez-Shibayama Christian, Besse Lenka, Cupovic Jovana, Künzler Patrizia, Boldanova Tuyana, Brand Stephan, Semela David, Duong François HT, Weston Christopher J, Ludewig Burkhard, Heim Markus H, Wendon Julia, Antoniades Charalambos G, Bernsmeier Christine (2019), Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis, in Life Science Alliance
, 3(1), e201900465-e201900465.
Bernsmeier Christine, Triantafyllou Evangelos, Brenig Robert, Lebosse Fanny J, Singanayagam Arjuna, Patel Vishal C, Pop Oltin T, Khamri Wafa, Nathwani Rooshi, Tidswell Robert, Weston Christopher J, Adams David H, Thursz Mark R, Wendon Julia A, Antoniades Charalambos Gustav (2018), CD14 + CD15 − HLA-DR − myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure, in Gut
, 67(6), 1155-1167.
Bernsmeier Christine, Albano Emanuele (2017), Liver dendritic cells and NAFLD evolution: A remaining open issue, in Journal of Hepatology
, 66(6), 1120-1122.
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) signalling 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) gut-derived 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.