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Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites
Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative me...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9421659/ https://www.ncbi.nlm.nih.gov/pubmed/36038551 http://dx.doi.org/10.1038/s41419-022-05186-w |
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author | Kusiak, Agnieszka A. Jakubowska, Monika A. Stopa, Kinga B. Zhang, Xiaoying Huang, Wei Gerasimenko, Julia V. Gerasimenko, Oleg V. Sutton, Robert Petersen, Ole H. Ferdek, Pawel E. |
author_facet | Kusiak, Agnieszka A. Jakubowska, Monika A. Stopa, Kinga B. Zhang, Xiaoying Huang, Wei Gerasimenko, Julia V. Gerasimenko, Oleg V. Sutton, Robert Petersen, Ole H. Ferdek, Pawel E. |
author_sort | Kusiak, Agnieszka A. |
collection | PubMed |
description | Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative metabolites, fatty acid ethyl esters, generated from ethanol and fatty acids. Although the role of non-oxidative alcohol metabolites and dysregulated Ca(2+) signalling in enzyme-storing pancreatic acinar cells is well established as the core mechanism of pancreatitis, signals in PSCs that trigger fibrogenesis are less clear. Here, we investigate real-time Ca(2+) signalling, changes in mitochondrial potential and cell death induced by ethanol metabolites in quiescent vs TGF-β-activated PSCs, compare the expression of Ca(2+) channels and pumps between the two phenotypes and the consequences these differences have on the pathogenesis of alcoholic pancreatitis. The extent of PSC activation in the pancreatitis of different aetiologies has been investigated in three animal models. Unlike biliary pancreatitis, alcohol-induced pancreatitis results in the activation of PSCs throughout the entire tissue. Ethanol and palmitoleic acid (POA) or palmitoleic acid ethyl ester (POAEE) act directly on quiescent PSCs, inducing cytosolic Ca(2+) overload, disrupting mitochondrial functions, and inducing cell death. However, activated PSCs acquire remarkable resistance against ethanol metabolites via enhanced Ca(2+)-handling capacity, predominantly due to the downregulation of the TRPA1 channel. Inhibition or knockdown of TRPA1 reduces EtOH/POA-induced cytosolic Ca(2+) overload and protects quiescent PSCs from cell death, similarly to the activated phenotype. Our results lead us to review current dogmas on alcoholic pancreatitis. While acinar cells and quiescent PSCs are prone to cell death caused by ethanol metabolites, activated PSCs can withstand noxious signals and, despite ongoing inflammation, deposit extracellular matrix components. Modulation of Ca(2+) signals in PSCs by TRPA1 agonists/antagonists could become a strategy to shift the balance of tissue PSCs towards quiescent cells, thus limiting pancreatic fibrosis. |
format | Online Article Text |
id | pubmed-9421659 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94216592022-08-30 Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites Kusiak, Agnieszka A. Jakubowska, Monika A. Stopa, Kinga B. Zhang, Xiaoying Huang, Wei Gerasimenko, Julia V. Gerasimenko, Oleg V. Sutton, Robert Petersen, Ole H. Ferdek, Pawel E. Cell Death Dis Article Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative metabolites, fatty acid ethyl esters, generated from ethanol and fatty acids. Although the role of non-oxidative alcohol metabolites and dysregulated Ca(2+) signalling in enzyme-storing pancreatic acinar cells is well established as the core mechanism of pancreatitis, signals in PSCs that trigger fibrogenesis are less clear. Here, we investigate real-time Ca(2+) signalling, changes in mitochondrial potential and cell death induced by ethanol metabolites in quiescent vs TGF-β-activated PSCs, compare the expression of Ca(2+) channels and pumps between the two phenotypes and the consequences these differences have on the pathogenesis of alcoholic pancreatitis. The extent of PSC activation in the pancreatitis of different aetiologies has been investigated in three animal models. Unlike biliary pancreatitis, alcohol-induced pancreatitis results in the activation of PSCs throughout the entire tissue. Ethanol and palmitoleic acid (POA) or palmitoleic acid ethyl ester (POAEE) act directly on quiescent PSCs, inducing cytosolic Ca(2+) overload, disrupting mitochondrial functions, and inducing cell death. However, activated PSCs acquire remarkable resistance against ethanol metabolites via enhanced Ca(2+)-handling capacity, predominantly due to the downregulation of the TRPA1 channel. Inhibition or knockdown of TRPA1 reduces EtOH/POA-induced cytosolic Ca(2+) overload and protects quiescent PSCs from cell death, similarly to the activated phenotype. Our results lead us to review current dogmas on alcoholic pancreatitis. While acinar cells and quiescent PSCs are prone to cell death caused by ethanol metabolites, activated PSCs can withstand noxious signals and, despite ongoing inflammation, deposit extracellular matrix components. Modulation of Ca(2+) signals in PSCs by TRPA1 agonists/antagonists could become a strategy to shift the balance of tissue PSCs towards quiescent cells, thus limiting pancreatic fibrosis. Nature Publishing Group UK 2022-08-29 /pmc/articles/PMC9421659/ /pubmed/36038551 http://dx.doi.org/10.1038/s41419-022-05186-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kusiak, Agnieszka A. Jakubowska, Monika A. Stopa, Kinga B. Zhang, Xiaoying Huang, Wei Gerasimenko, Julia V. Gerasimenko, Oleg V. Sutton, Robert Petersen, Ole H. Ferdek, Pawel E. Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites |
title | Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites |
title_full | Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites |
title_fullStr | Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites |
title_full_unstemmed | Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites |
title_short | Activation of pancreatic stellate cells attenuates intracellular Ca(2+) signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites |
title_sort | activation of pancreatic stellate cells attenuates intracellular ca(2+) signals due to downregulation of trpa1 and protects against cell death induced by alcohol metabolites |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9421659/ https://www.ncbi.nlm.nih.gov/pubmed/36038551 http://dx.doi.org/10.1038/s41419-022-05186-w |
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