Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target.

Abstract

Cholangiopathies are a group of diseases mainly including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), biliary atresia (BA), and cholangiocarcinoma (CCA). Very limited treatment options are available for these diseases. Following an injury and exposure to DAMPs (Damage associated molecular patterns) and/or PAMPs (Pathogen-associated molecular patterns), cholangiocytes produce a variety of pro-inflammatory cytokines/chemokines leading to the activation of other innate and also adaptive immune cells. Over the past decade, the emergence of trained immunity, a de facto"innate immune memory", suggested a novel therapeutic targeting in several diseases including autoimmune diseases. Trained immunity enables innate immunity cells the ability to generate a rapid and changed response when exposed to the secondary stimuli. These abilities are orchestrated by metabolic and epigenetic changes. Metabolic changes are carried out by an increase in glycolysis through the PI3K/AKT/mTOR/ HIF-1α pathway whereas epigenetic modifications are mediated by DNA methylation and histone modification during cholangiopathies. A better understanding and knowledge of the pathophysiology of cholangiopathies and of the mechanisms involved in trained immunity would represent a major step forward in the search for novel treatment of cholangiopathies. In conclusion, we hypothesize that such induction of trained immunity in cholangiocytes and innate immune cells may result in the deregulation of pro-inflammatory cytokine production, which leads to over-activation of innate and adaptive immune cells, resulting in the destruction of cholangiocytes. In this review, we will highlight the recent advances in the knowledge of cholangiopathies underlying the mechanisms that trained immunity is involved, which may provide novel therapeutic targets in cholangiopathies.