Modulation of MER tyrosine kinase signalling in liver failure: A therapeutic strategy to reverse immuneparesis and susceptibility to infection. (360G-Wellcome-107303_Z_15_Z)

Sepsis is a major cause of mortality for patients suffering from acute-on-chronic liver failure (ACLF). My preliminary data demonstrates a pivotal role for MERTK signalling in suppression of monocytes/macrophages immune responses to microbial challenge, increasing susceptibility to infections. Objectives: We will test the hypothesis that MERTK positive monocytes/macrophages are functionally hyporesponsive to microbial challenge, resulting in infection susceptibility across compartments, with e xploration of the autocrine and paracrine mechanisms suggested in our preliminary data. We will study the factors that influence MERTK expression as monocytes migrate across endothelia. Finally, we will investigate the potential for timely MERTK inhibition to reverse immune defects. Methods: Monocytes/macrophages from circulation, liver, lymph nodes and peritoneum from patients with ACLF and comparator groups will be isolated, and analysed using FACS-based techniques. Transendothelial migration will be assessed using cell migration models. Downstream effects of MERTK-agonists/antagonists on the MERTK signalling pathway will be evaluated in vitro. Using this data, we will evaluate the efficacy of inhibiting MERTK signalling as a strategy to restore ex-vivo monocyte function in ACLF patients, providing proof-of principle data for development of this as a novel therapeutic strategy to reverse immuneparesis, reducing susceptibility to infection and improve the outcome of this devastating condition.