Mechanisms of cholangiocyte responses to injury

Abstract

Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Cholangiocyte‐Derived Exosomal Long Noncoding RNA H19 Promotes Hepatic Stellate Cell Activation and Cholestatic Liver Fibrosis

“…Obstruction of bile flow results in the accumulation of bile acids, which not only causes hepatic cell injury and chronic inflammation but also induces ductular reaction as characterized by the cholangiocyte proliferation and bile duct hyperplasia . It is well established that aberrant inflammation induces the activation of HSCs and promotes liver fibrosis progression . However, whether and how cholangiocytes affect HSC transdifferentiation or activation remains to be fully elucidated.…”

Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

“…Cholangiocytes are the primary targets in the pathogenesis of cholestatic liver diseases. Biliary obstruction and abnormal bile formation result in the accumulation of bile acids, which causes progressive bile duct destruction and hepatic inflammation, and further contributes to fibrosis, cirrhosis, and eventually liver failure [35][36][37]. It has been well documented that hepatic inflammation is an essential driving force for liver fibrosis by recruiting inflammatory cells and activating HSCs [33,38].…”

Innate Immunity and Pathogenesis of Biliary Atresia

“…Biliary epithelial cells (cholangiocytes) are not only a physical barrier that drains the bile into the duodenum but they are also immunocompetent cells involved in tissue homeostasis, capable of recognizing microbial conserved motifs known as Pathogen Associated Molecular Patterns (PAMPs) through patternrecognition receptors (PRRs) and initiating an inflammatory response (64)(65)(66)(67). Four main families of PRRs have been described, including toll-like receptors (TLRs), retinoic acid inducible gene 1 (RIG-I)-like receptors (RLRs), nucleotidebinding oligomerization domain (NOD)-like receptors (NLRs), and C-type lectin receptors (CLRs) (68).…”