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

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...

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Autores principales: Zhou, Tianhao, Meadows, Vik, Kundu, Debjyoti, Kyritsi, Konstantina, Owen, Travis, Ceci, Ludovica, Carpino, Guido, Onori, Paolo, Gaudio, Eugenio, Wu, Nan, Glaser, Shannon, Ekser, Burcin, Alpini, Gianfranco, Kennedy, Lindsey, Francis, Heather
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512472/
https://www.ncbi.nlm.nih.gov/pubmed/35799467
http://dx.doi.org/10.1002/hep4.2026
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author Zhou, Tianhao
Meadows, Vik
Kundu, Debjyoti
Kyritsi, Konstantina
Owen, Travis
Ceci, Ludovica
Carpino, Guido
Onori, Paolo
Gaudio, Eugenio
Wu, Nan
Glaser, Shannon
Ekser, Burcin
Alpini, Gianfranco
Kennedy, Lindsey
Francis, Heather
author_facet Zhou, Tianhao
Meadows, Vik
Kundu, Debjyoti
Kyritsi, Konstantina
Owen, Travis
Ceci, Ludovica
Carpino, Guido
Onori, Paolo
Gaudio, Eugenio
Wu, Nan
Glaser, Shannon
Ekser, Burcin
Alpini, Gianfranco
Kennedy, Lindsey
Francis, Heather
author_sort Zhou, Tianhao
collection PubMed
description 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.
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spelling pubmed-95124722022-09-30 Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling Zhou, Tianhao Meadows, Vik Kundu, Debjyoti Kyritsi, Konstantina Owen, Travis Ceci, Ludovica Carpino, Guido Onori, Paolo Gaudio, Eugenio Wu, Nan Glaser, Shannon Ekser, Burcin Alpini, Gianfranco Kennedy, Lindsey Francis, Heather Hepatol Commun Original Articles 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. John Wiley and Sons Inc. 2022-07-07 /pmc/articles/PMC9512472/ /pubmed/35799467 http://dx.doi.org/10.1002/hep4.2026 Text en © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Zhou, Tianhao
Meadows, Vik
Kundu, Debjyoti
Kyritsi, Konstantina
Owen, Travis
Ceci, Ludovica
Carpino, Guido
Onori, Paolo
Gaudio, Eugenio
Wu, Nan
Glaser, Shannon
Ekser, Burcin
Alpini, Gianfranco
Kennedy, Lindsey
Francis, Heather
Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling
title Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling
title_full Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling
title_fullStr Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling
title_full_unstemmed Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling
title_short Mast cells selectively target large cholangiocytes during biliary injury via H2HR‐mediated cAMP/pERK1/2 signaling
title_sort mast cells selectively target large cholangiocytes during biliary injury via h2hr‐mediated camp/perk1/2 signaling
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512472/
https://www.ncbi.nlm.nih.gov/pubmed/35799467
http://dx.doi.org/10.1002/hep4.2026
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