monocytes - macrophages – cirrhosis - liver failure – TAM receptors

Translational Hepatology

Monocyte and macrophage biology in cirrhosis of the liver

Cirrhosis of the liver is a systemic condition depicted by its high morbidity and mortality and raising prevalence worldwide. There is no treatment option other than transplantation, applicable to only a minority of patients. Infectious complications are highly frequent and independent predictors of adverse prognosis - being the leading cause of acute decompensation, ‘acute-on-chronic’ liver failure (ACLF) and death. Infection susceptibility in cirrhosis has been attributed to a state termed “immuneparesis” and monocyte and macrophage dysfunction, defined by defective immune responses to microbial challenge. A detailed understanding of the mechanisms underlying immuneparesis in patients with cirrhosis is desired in order to identify prognostic markers and define potential future immunotherapeutic targets that may enhance innate immune responses and reduce the need for liver transplantation and death.

Our research team seeks to decipher the pathophysiology of immuneparesis and monocyte and macrophage dysfunction in patients with cirrhosis. Specifically we focus on receptor tyrosine kinases of the TAM receptor family (Tyro-3, AXL and MERTK), expressed on monocytes and macrophages, which play a pivotal role in regulating innate immune responses. We have recently discovered the expansion of circulating immune-regulatory AXL- and MERTK-expressing monocyte subsets in patients with cirrhosis at different stages that suppressed cytokine responses (TNF-α and IL-6) to lipopolysaccharide. Also other monocyte functions of the distinct subsets were modified. In advanced stages of cirrhosis these dysfunctional subsets may prevail and lead to reduced capacity to repel microbial challenge and infection susceptibility. We aim to understand as to how differential TAM receptor signalling is regulated in the progression from compensated to decompensated cirrhosis and controls innate immune responses. We further investigate whether specific inhibition of TAM receptor signalling can restore innate immune responses of monocytes from patients with cirrhosis.