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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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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. |
format | Online Article Text |
id | pubmed-9512472 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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