MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation

Oihane Erice, Patricia Munoz-Garrido, Javier Vaquero, Maria J. Perugorria, Maite G. Fernandez-Barrena, Elena Saez, Alvaro Santos-Laso, Ander Arbelaiz, Raul Jimenez-Agüero, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Verónica Torrano, Arkaitz Carracedo, Meenakshisundaram Ananthanarayanan, Marco Marzioni, Jesus Prieto, Ulrich Beuers, Ronald P. Oude Elferink, Nicholas F La Russo, Luis BujandaJose J.G. Marin, Jesus M. Banales

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl-/ HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion: Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - Jan 1 2018

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Cholangitis
MicroRNAs
Dihydrolipoyllysine-Residue Acetyltransferase
Chloride-Bicarbonate Antiporters
Cytokines
Biological Phenomena
Intrahepatic Bile Ducts
Inositol 1,4,5-Trisphosphate Receptors
Interleukin-18
Endoplasmic Reticulum Stress
Liver
Cholestasis
Interleukin-12
Coculture Techniques
Luciferases
Bile Acids and Salts
Interleukin-8
Human Activities
Cell Adhesion
Caspase 3

ASJC Scopus subject areas

  • Hepatology

Cite this

Erice, O., Munoz-Garrido, P., Vaquero, J., Perugorria, M. J., Fernandez-Barrena, M. G., Saez, E., ... Banales, J. M. (Accepted/In press). MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation. Hepatology. https://doi.org/10.1002/hep.29533

MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation. / Erice, Oihane; Munoz-Garrido, Patricia; Vaquero, Javier; Perugorria, Maria J.; Fernandez-Barrena, Maite G.; Saez, Elena; Santos-Laso, Alvaro; Arbelaiz, Ander; Jimenez-Agüero, Raul; Fernandez-Irigoyen, Joaquin; Santamaria, Enrique; Torrano, Verónica; Carracedo, Arkaitz; Ananthanarayanan, Meenakshisundaram; Marzioni, Marco; Prieto, Jesus; Beuers, Ulrich; Oude Elferink, Ronald P.; La Russo, Nicholas F; Bujanda, Luis; Marin, Jose J.G.; Banales, Jesus M.

In: Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

Erice, O, Munoz-Garrido, P, Vaquero, J, Perugorria, MJ, Fernandez-Barrena, MG, Saez, E, Santos-Laso, A, Arbelaiz, A, Jimenez-Agüero, R, Fernandez-Irigoyen, J, Santamaria, E, Torrano, V, Carracedo, A, Ananthanarayanan, M, Marzioni, M, Prieto, J, Beuers, U, Oude Elferink, RP, La Russo, NF, Bujanda, L, Marin, JJG & Banales, JM 2018, 'MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation', Hepatology. https://doi.org/10.1002/hep.29533
Erice O, Munoz-Garrido P, Vaquero J, Perugorria MJ, Fernandez-Barrena MG, Saez E et al. MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation. Hepatology. 2018 Jan 1. https://doi.org/10.1002/hep.29533
Erice, Oihane ; Munoz-Garrido, Patricia ; Vaquero, Javier ; Perugorria, Maria J. ; Fernandez-Barrena, Maite G. ; Saez, Elena ; Santos-Laso, Alvaro ; Arbelaiz, Ander ; Jimenez-Agüero, Raul ; Fernandez-Irigoyen, Joaquin ; Santamaria, Enrique ; Torrano, Verónica ; Carracedo, Arkaitz ; Ananthanarayanan, Meenakshisundaram ; Marzioni, Marco ; Prieto, Jesus ; Beuers, Ulrich ; Oude Elferink, Ronald P. ; La Russo, Nicholas F ; Bujanda, Luis ; Marin, Jose J.G. ; Banales, Jesus M. / MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation. In: Hepatology. 2018.
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abstract = "Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl-/ HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion: Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients.",
author = "Oihane Erice and Patricia Munoz-Garrido and Javier Vaquero and Perugorria, {Maria J.} and Fernandez-Barrena, {Maite G.} and Elena Saez and Alvaro Santos-Laso and Ander Arbelaiz and Raul Jimenez-Ag{\"u}ero and Joaquin Fernandez-Irigoyen and Enrique Santamaria and Ver{\'o}nica Torrano and Arkaitz Carracedo and Meenakshisundaram Ananthanarayanan and Marco Marzioni and Jesus Prieto and Ulrich Beuers and {Oude Elferink}, {Ronald P.} and {La Russo}, {Nicholas F} and Luis Bujanda and Marin, {Jose J.G.} and Banales, {Jesus M.}",
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T1 - MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation

AU - Erice, Oihane

AU - Munoz-Garrido, Patricia

AU - Vaquero, Javier

AU - Perugorria, Maria J.

AU - Fernandez-Barrena, Maite G.

AU - Saez, Elena

AU - Santos-Laso, Alvaro

AU - Arbelaiz, Ander

AU - Jimenez-Agüero, Raul

AU - Fernandez-Irigoyen, Joaquin

AU - Santamaria, Enrique

AU - Torrano, Verónica

AU - Carracedo, Arkaitz

AU - Ananthanarayanan, Meenakshisundaram

AU - Marzioni, Marco

AU - Prieto, Jesus

AU - Beuers, Ulrich

AU - Oude Elferink, Ronald P.

AU - La Russo, Nicholas F

AU - Bujanda, Luis

AU - Marin, Jose J.G.

AU - Banales, Jesus M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl-/ HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion: Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients.

AB - Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although its etiopathogenesis remains obscure, development of antimitochondrial autoantibodies against pyruvate dehydrogenase complex E2 is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but its functional relevance is largely unknown. We previously reported that miR-506 is overexpressed in PBC cholangiocytes and directly targets both Cl-/ HCO3- anion exchanger 2 and type III inositol 1,4,5-trisphosphate receptor, leading to cholestasis. Here, the regulation of miR-506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several proinflammatory cytokines overexpressed in PBC livers (such as interleukin-8 [IL8], IL12, IL17, IL18, and tumor necrosis factor alpha) stimulated miR-506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR-506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR-506 (1) induced dedifferentiation with down-regulation of biliary and epithelial markers together with up-regulation of mesenchymal, proinflammatory, and profibrotic markers; (2) impaired cell proliferation and adhesion; (3) increased oxidative and endoplasmic reticulum stress; (4) caused DNA damage; and (5) sensitized to caspase-3-dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less adenosine triphosphate production) and pyruvate dehydrogenase complex E2 overexpression. Coculture of miR-506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion: Different proinflammatory cytokines enhance the expression of miR-506 in biliary epithelial cells; miR-506 induces PBC-like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients.

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