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<p>Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific <i>Rage</i> activity in fostering a pro-fibrotic milieu. <i>RAGE</i> is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a <i>Rage</i>-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.</p>

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RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月2日

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  • Wai-Ling Macrina Lam,
  • Gisela Gabernet,
  • Tanja Poth,
  • Melanie Sator-Schmitt,
  • Morgana Barroso Oquendo,
  • Bettina Kast,
  • Sabrina Lohr,
  • Aurora de Ponti,
  • Lena Weiß,
  • Martin Schneider,
  • Dominic Helm,
  • Karin Müller-Decker,
  • Peter Schirmacher,
  • Mathias Heikenwälder,
  • Ursula Klingmüller,
  • Doris Schneller,
  • Fabian Geisler,
  • Sven Nahnsen,
  • Peter Angel

摘要

Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.