title: The Receptor for Advanced Glycation End Products (RAGE) controls ductular reaction-mediated fibrosis during cholestasis
creator: Lam, Wai Ling Macrina
subject: ddc-570
subject: 570 Life sciences
description: Hepatic fibrosis is implicated in most etiologies of chronic liver diseases (CLD). It is a pathological process resembling a wound repair response, which is characterized by hepatic stellate cells (HSCs) activation and excessive production and deposition of extracellular matrix (ECM), which elicits substantial tissue scarring and impairment of liver function. Ductular reaction (DR) is a common clinical manifestation observed among most of the etiologies of CLD, but most prevalent in cholangiopathies, including cholestasis, primary biliary cholangitis and primary sclerosing cholangitis. It refers to the proliferative response of the biliary epithelial cells (BECs) that line the bile ducts in the biliary systems. DR is commonly associated with increased risk of fibrosis. On the contrary, DR is thought to serve as a regenerative mechanism to compensate for the anatomical or functional loss of the biliary system in the damaged liver. In view of the conflicting results from earlier studies, it remains elusive how DR and fibrogenic events are linked with each other.     The Receptor for Advanced Glycation End Products (RAGE) is an immunoglobulin and pattern recognition receptor that interacts with a variety of ligands, including the advanced glycation end products, HMGB1 and S100 proteins, which are released by damaged tissues and activated immune cells. In an environment with persistent stress, the accumulated RAGE ligands interact with RAGE and activates multiple pro-proliferation and inflammatory pathways, including Janus kinase (JAK)/ signal transducers and activators of transcript (STAT), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT and nuclear factor-κB (NFκB) pathways, thus sustaining inflammatory responses. Apart from playing a pivotal role in modulating the tissue microenvironment, earlier studies have also demonstrated RAGE in acting as a critical direct or indirect mediator of BEC expansion and onset of fibrosis during chronic injury.    In this dissertation, the specific function of RAGE on BECs in DR and its potential association with fibrosis in the context of cholestasis was elucidated by both in vivo and in vitro approaches. To examine the role of BEC-specific RAGE activity under cholestatic condition in vivo, Rage was conditionally deleted in BECs in a biliary tracing reporter murine model R26TomHnf1bCreER, followed by administration of choline-deficient ethionine-supplemented (CDE) diet for three weeks. In CDE-induced cholestatic condition, RAGE deficiency in BECs strongly impaired DR, alongside a substantial reduction of stellate cell activation and attenuation of bridging fibrosis. RNA-seq data of primary BECs isolated from CDE-challenged mice revealed a RAGE-dependent mechanistic role of BECs in ECM remodeling and HSC activation. In line with the in vivo results, the in vitro analyses demonstrated an interplay between BECs and HSCs dependent on BEC-specific RAGE activity. To be more specific, it uncovered Jag1 mRNA expression and secretory proteins were released by BEC in a RAGE-dependent manner. BEC-derived secretory JAG1 activates Notch signaling in HSCs in trans, and enhances the transformation of HSCs into a myofibroblastic-like status, thus establishes a pro-fibrotic milieu. All in all, my present study contributes to an increased understanding of the adverse consequence of DR in cholestasis-associated fibrosis and may guide future studies on new anti-fibrotic therapeutic strategies for unmet medical needs.
date: 2024
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/33033/1/LAM_Wai_Ling_Macrina_Dissertation.pdf
identifier: DOI:10.11588/heidok.00033033
identifier: urn:nbn:de:bsz:16-heidok-330331
identifier:   Lam, Wai Ling Macrina  (2024) The Receptor for Advanced Glycation End Products (RAGE) controls ductular reaction-mediated fibrosis during cholestasis.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33033/
rights: info:eu-repo/semantics/openAccess
rights: Please see front page of the work (Sorry, Dublin Core plugin does not recognise license id)
language: eng