Cholangiokines: undervalued modulators in the hepatic microenvironment

Abstract

The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes.

Cholangiocyte RAGE drives the ductular reaction which provides biliary drainage but fuels liver injury

“…Immunolabeled liver sections were cleared with a modified version of the 3DISCO protocol (5). All steps were performed at RT on a shaking device.…”

“…These damaged hepatocytes release damage-associated molecular patterns (DAMPs) in the form of proteins such as S100, HMGB1 or small molecules such as quinolinic acid 3 . DAMPs trigger the DR through pattern recognition receptors expressed on the apical membrane of epithelial cells 4 such as hepatocytes and cholangiocytes 5 . Despite the DR being a common and prominent feature of nearly all liver pathologies, its functional importance remains unclear.…”

LP340, a novel histone deacetylase inhibitor, decreases liver injury and fibrosis in mice: role of oxidative stress and microRNA-23a

“…Experimental and clinical evidence shows that oxidative stress also plays a critical role in the development of fibrosis by stimulating/amplifying inflammatory and profibrotic responses via increased expression and activation of Frontiers in Pharmacology frontiersin.org 10 proinflammatory/profibrotic mediators (e.g., TNFα, TGFβ, IL-1β) (Sanchez-Valle et al, 2012;Allameh et al, 2023). Oxidative stress also causes senescence in cholangiocytes and stimulates senescence-related bile ductular reactions, thus causing release of cholangiokines (e.g., TGFβ, connective tissue growth factor) that stimulate fibrosis in cholestatic liver disease (Nakanuma et al, 2015;Carpino et al, 2017;Sato et al, 2019;Cai et al, 2023). ROS and products of lipid peroxidation stimulate quiescent HSC to transdifferentiate into an activated, highly proliferative myofibroblast-like phenotype (Svegliati-Baroni et al, 2001a;Svegliati-Baroni et al, 2001b;Gandhi, 2012).…”

Cellular heterogeneity and plasticity during NAFLD progression

“…These secreted inflammatory factors activate and recruit immune cells. Liver mesenchymal cells are also activated by these inflammatory signals from the bile duct and are attracted to the bile duct ( Cai et al, 2023 ). Activated mesenchymal cells secrete vesicles and soluble paracrine factors and stimulate cells in the bile ( Banales et al, 2019 ; Azparren-Angulo et al, 2021 ).…”