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Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse
BACKGROUND & AIMS: Cholangiocyte senescence is important in the pathogenesis of primary sclerosing cholangitis (PSC). We found that CDKN2A (p16), a cyclin-dependent kinase inhibitor and mediator of senescence, was increased in cholangiocytes of patients with PSC and from a PSC mouse model (multi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044431/ https://www.ncbi.nlm.nih.gov/pubmed/33870156 http://dx.doi.org/10.1016/j.jhepr.2021.100250 |
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author | Alsuraih, Mohammed O’Hara, Steven P. Woodrum, Julie E. Pirius, Nicholas E. LaRusso, Nicholas F. |
author_facet | Alsuraih, Mohammed O’Hara, Steven P. Woodrum, Julie E. Pirius, Nicholas E. LaRusso, Nicholas F. |
author_sort | Alsuraih, Mohammed |
collection | PubMed |
description | BACKGROUND & AIMS: Cholangiocyte senescence is important in the pathogenesis of primary sclerosing cholangitis (PSC). We found that CDKN2A (p16), a cyclin-dependent kinase inhibitor and mediator of senescence, was increased in cholangiocytes of patients with PSC and from a PSC mouse model (multidrug resistance 2; Mdr2(-/-)). Given that recent data suggest that a reduction of senescent cells is beneficial in different diseases, we hypothesised that inhibition of cholangiocyte senescence would ameliorate disease in Mdr2(-/-) mice. METHODS: We used 2 novel genetic murine models to reduce cholangiocyte senescence: (i) p16(Ink4a) apoptosis through targeted activation of caspase (INK-ATTAC)xMdr2(-/-), in which the dimerizing molecule AP20187 promotes selective apoptotic removal of p16-expressing cells; and (ii) mice deficient in both p16 and Mdr2. Mdr2(-/-) mice were also treated with fisetin, a flavonoid molecule that selectively kills senescent cells. p16, p21, and inflammatory markers (tumour necrosis factor [TNF]-α, IL-1β, and monocyte chemoattractant protein-1 [MCP-1]) were measured by PCR, and hepatic fibrosis via a hydroxyproline assay and Sirius red staining. RESULTS: AP20187 treatment reduced p16 and p21 expression by ~35% and ~70% (p >0.05), respectively. Expression of inflammatory markers (TNF-α, IL-1β, and MCP-1) decreased (by 60%, 40%, and 60%, respectively), and fibrosis was reduced by ~60% (p >0.05). Similarly, p16(-/-)xMdr2(-/-) mice exhibited reduced p21 expression (70%), decreased expression of TNF-α, IL-1β (60%), and MCP-1 (65%) and reduced fibrosis (~50%) (p >0.05) compared with Mdr2(-/-) mice. Fisetin treatment reduced expression of p16 and p21 (80% and 90%, respectively), TNF-α (50%), IL-1β (50%), MCP-1 (70%), and fibrosis (60%) (p >0.05). CONCLUSIONS: Our data support a pathophysiological role of cholangiocyte senescence in the progression of PSC, and that targeted removal of senescent cholangiocytes is a plausible therapeutic approach. LAY SUMMARY: Primary sclerosing cholangitis is a fibroinflammatory, incurable biliary disease. We previously reported that biliary epithelial cell senescence (cell-cycle arrest and hypersecretion of profibrotic molecules) is an important phenotype in primary sclerosing cholangitis. Herein, we demonstrate that reducing the number of senescent cholangiocytes leads to a reduction in the expression of inflammatory, fibrotic, and senescence markers associated with the disease. |
format | Online Article Text |
id | pubmed-8044431 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-80444312021-04-16 Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse Alsuraih, Mohammed O’Hara, Steven P. Woodrum, Julie E. Pirius, Nicholas E. LaRusso, Nicholas F. JHEP Rep Research Article BACKGROUND & AIMS: Cholangiocyte senescence is important in the pathogenesis of primary sclerosing cholangitis (PSC). We found that CDKN2A (p16), a cyclin-dependent kinase inhibitor and mediator of senescence, was increased in cholangiocytes of patients with PSC and from a PSC mouse model (multidrug resistance 2; Mdr2(-/-)). Given that recent data suggest that a reduction of senescent cells is beneficial in different diseases, we hypothesised that inhibition of cholangiocyte senescence would ameliorate disease in Mdr2(-/-) mice. METHODS: We used 2 novel genetic murine models to reduce cholangiocyte senescence: (i) p16(Ink4a) apoptosis through targeted activation of caspase (INK-ATTAC)xMdr2(-/-), in which the dimerizing molecule AP20187 promotes selective apoptotic removal of p16-expressing cells; and (ii) mice deficient in both p16 and Mdr2. Mdr2(-/-) mice were also treated with fisetin, a flavonoid molecule that selectively kills senescent cells. p16, p21, and inflammatory markers (tumour necrosis factor [TNF]-α, IL-1β, and monocyte chemoattractant protein-1 [MCP-1]) were measured by PCR, and hepatic fibrosis via a hydroxyproline assay and Sirius red staining. RESULTS: AP20187 treatment reduced p16 and p21 expression by ~35% and ~70% (p >0.05), respectively. Expression of inflammatory markers (TNF-α, IL-1β, and MCP-1) decreased (by 60%, 40%, and 60%, respectively), and fibrosis was reduced by ~60% (p >0.05). Similarly, p16(-/-)xMdr2(-/-) mice exhibited reduced p21 expression (70%), decreased expression of TNF-α, IL-1β (60%), and MCP-1 (65%) and reduced fibrosis (~50%) (p >0.05) compared with Mdr2(-/-) mice. Fisetin treatment reduced expression of p16 and p21 (80% and 90%, respectively), TNF-α (50%), IL-1β (50%), MCP-1 (70%), and fibrosis (60%) (p >0.05). CONCLUSIONS: Our data support a pathophysiological role of cholangiocyte senescence in the progression of PSC, and that targeted removal of senescent cholangiocytes is a plausible therapeutic approach. LAY SUMMARY: Primary sclerosing cholangitis is a fibroinflammatory, incurable biliary disease. We previously reported that biliary epithelial cell senescence (cell-cycle arrest and hypersecretion of profibrotic molecules) is an important phenotype in primary sclerosing cholangitis. Herein, we demonstrate that reducing the number of senescent cholangiocytes leads to a reduction in the expression of inflammatory, fibrotic, and senescence markers associated with the disease. Elsevier 2021-01-27 /pmc/articles/PMC8044431/ /pubmed/33870156 http://dx.doi.org/10.1016/j.jhepr.2021.100250 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Alsuraih, Mohammed O’Hara, Steven P. Woodrum, Julie E. Pirius, Nicholas E. LaRusso, Nicholas F. Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse |
title | Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse |
title_full | Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse |
title_fullStr | Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse |
title_full_unstemmed | Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse |
title_short | Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2(-/-) mouse |
title_sort | genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the mdr2(-/-) mouse |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044431/ https://www.ncbi.nlm.nih.gov/pubmed/33870156 http://dx.doi.org/10.1016/j.jhepr.2021.100250 |
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