Reactive cholangiocyte-derived ORM2 drives a pathogenic modulation of the injured biliary niche through macrophage reprogramming

作者：Hanyang Liu, Guo Yin, Bianca Franco Leonardi, Tian Lan, Yeni Ait Ahmed, Hilmar Berger, Marlene Kohlhepp, Natalja Amiridze, Natalia Martagón Calderón, Carla Frau, Ludovic Vallier, Milad Rezvani, Frank Tacke, Adrien Guillot · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2024-334425 · 被引用次数：21 · 研究领域：Liver physiology and pathology、Organ Transplantation Techniques and Outcomes、Liver Diseases and Immunity

Background Injured or reactive biliary epithelial cells participate in most chronic liver injuries in a process referred to as ductular reaction, which involves multicellular interactions with marked local infiltration of macrophages and fibrogenic cell activation. The direct roles of biliary epithelial cells in shaping their cellular niche remain unknown. Objective We aimed at investigating the effects of biliary epithelial cell-derived acute phase response protein orosomucoid 2 (ORM2) in shaping monocyte/macrophage response to liver injury. Design Transcriptome data sets from human and mouse livers were used, results were confirmed with multiplex immunofluorescence. A multicellular biliary-niche-on-a-chip derived from primary liver and blood cells (wild-type, Mdr2 −/− mice) was established to model ductular reaction. Human blood cells collected from healthy donors and intrahepatic cholangiocyte organoids derived from normal and cirrhotic liver patients were used. Results Our transcriptome data set and multiplex immunofluorescence analyses indicated a previously unrecognised involvement of the acute phase response protein ORM2 in ductular reactions in both human and mouse livers. ORM2 gene expression was increased in biliatresone-challenged, bile acid-challenged and acetaminophen-challenged cholangiocytes. Cholangiocyte-derived ORM2 induced unique transcriptome changes and functional adaptation of liver macrophages. ORM2-activated macrophages exacerbated cholangiocyte cell s...