Mast cells selectively target large cholangiocytes during biliary injury via H2HR-mediated cAMP/pERK1/2 signaling.

Autor: Zhou T; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Meadows V; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Kundu D; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Kyritsi K; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Owen T; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Ceci L; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Carpino G; Department of MovementHuman and Health SciencesUniversity of Rome 'Foro Italico'RomeItaly., Onori P; Department of Anatomical, HistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly., Gaudio E; Department of Anatomical, HistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly., Wu N; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA., Glaser S; Department of Medical PhysiologyTexas A&M UniversityBryanTexasUSA., Ekser B; Division of Transplant SurgeryDepartment of SurgeryIndiana University School of MedicineIndianapolisIndianaUSA., Alpini G; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA.; Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA., Kennedy L; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA.; Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA., Francis H; Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of Medicine ResearchIndianapolisIndianaUSA.; Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2022 Oct; Vol. 6 (10), pp. 2715-2731. Date of Electronic Publication: 2022 Jul 07.
DOI: 10.1002/hep4.2026
Abstrakt: Bile ducts are heterogenous in structure and function, and primary sclerosing cholangitis (PSC) damages specific bile ducts leading to ductular reaction (DR), mast cell (MC) infiltration, increased histamine release, inflammation, and fibrosis. Bile duct ligation (BDL) induces large duct damage via cyclic adenosine monophosphate (cAMP)/extracellular signal-related protein kinase (ERK) signaling, and large cholangiocytes express H2 histamine receptor (H2HR). We evaluated how MCs interact with large cholangiocytes during cholestasis. Male wild-type (WT) and MC-deficient (Kit W-sh ) mice 10-12 weeks of age were subjected to BDL for 7 days. Select Kit W-sh mice were injected with MCs pretreated with control or H2HR antagonist (ranitidine, 25 μm, 48 h) via tail vein injection. In vitro, MC migration toward small mouse cholangiocytes (SMCCs) and large mouse cholangiocytes (LMCCs) treated with lipopolysaccharide or histamine (±ranitidine) was measured. LMCCs were stimulated with MC supernatants pretreated with control, α-methyl-dl-histidine (to block histamine release), or ranitidine. Liver damage, large duct DR/senescence, inflammation, fibrosis, and cAMP/ERK immunoreactivity increased in BDL WT and Kit W-sh +MC mice but decreased in BDL Kit W-sh and Kit W-sh +MC-H2HR mice. In vitro, MCs migrate toward damaged LMCCs (but not SMCCs) blocked by inhibition of H2HR. Loss of MC histamine or MC-H2HR decreases LMCC proliferation, senescence, H2HR, and cAMP/ERK levels. Human PSC livers have increased MC number found near DR, senescent ducts, and H2HR-positive ducts. Conclusion: Infiltrating MCs preferentially interact with large ducts via H2HR signaling promoting biliary and liver damage. Mediation of MCs may be a therapeutic strategy for PSC.
(© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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