Immune cell composition in cholangiopathies: Target and modulator of gut-to-liver signals in cholestatic liver injury

Although inflammation appears to be a driver of cholestatic liver disease progression, the exact mechanisms linking biliary injury, inflammation and fibrosis remain poorly understood. Remarkable changes in the composition of the gut microbiota in patients with primary sclerosing cholangitis (PSC) and other biliary diseases suggest have been reported, suggesting that dysbiosis may be crucial for cholangiopathy pathogenesis or progression. Moreover, approximately 80% of PSC patients suffer from inflammatory bowel disease. In this study, using mouse models of biliary and/or intestinal injury as well as human samples, we aimed at identifying potential cellular actors implicated in cholangiopathy progression. We investigated the consequences of dextran sulfate sodium (DSS)-induced colitis on liver, colon and blood immune cell populations in a murine model of PSC (Mdr2-/- mice). We characterized the in situ expression of pattern recognition receptors (PRRs) in various cell populations with an innovative multiplex immunostaining protocol. Moreover, we validated a 27 marker panel for flow cytometry to further define these populations. Similar approaches were applied to PSC patient blood samples to correlate changes in immune cell populations with the severity of the disease. So far, we evidenced that PRRs are expressed by virtually all immune cells and some othert cells, notably toll-like receptor 4 (TLR4) by endothelial cells. In the liver, concomitant colitis induces changes in neutrophil infiltration, which particularly express TLR9, and higher TLR4 expression is observed on infiltrating monocytes. Our findings may imply that the gut-liver axis modulates hepatic inflammation and disease progression in cholangiopathies.

Publication History

Article published online:
26 January 2022