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Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop
Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190839/ https://www.ncbi.nlm.nih.gov/pubmed/29665074 http://dx.doi.org/10.1002/glia.23337 |
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author | Mouton‐Liger, François Rosazza, Thibault Sepulveda‐Diaz, Julia Ieang, Amélie Hassoun, Sidi‐Mohamed Claire, Emilie Mangone, Graziella Brice, Alexis Michel, Patrick P. Corvol, Jean‐Christophe Corti, Olga |
author_facet | Mouton‐Liger, François Rosazza, Thibault Sepulveda‐Diaz, Julia Ieang, Amélie Hassoun, Sidi‐Mohamed Claire, Emilie Mangone, Graziella Brice, Alexis Michel, Patrick P. Corvol, Jean‐Christophe Corti, Olga |
author_sort | Mouton‐Liger, François |
collection | PubMed |
description | Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow‐derived macrophages from Park2(−/−) and Pink1(−/−) mice. The caspase 1‐dependent release of IL‐1β and IL‐18 was, therefore, enhanced in Park2(−/−) and Pink1(−/−) cells. This defect was confirmed in blood‐derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin‐deficient cells was accompanied by a lack of induction of A20, a well‐known negative regulator of the NF‐κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL‐1β release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3‐inflammasome axis participates in the pathogenesis of PARK2‐linked PD, paving the way for the exploration of its potential as a biomarker and treatment target. |
format | Online Article Text |
id | pubmed-6190839 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61908392018-10-22 Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop Mouton‐Liger, François Rosazza, Thibault Sepulveda‐Diaz, Julia Ieang, Amélie Hassoun, Sidi‐Mohamed Claire, Emilie Mangone, Graziella Brice, Alexis Michel, Patrick P. Corvol, Jean‐Christophe Corti, Olga Glia Research Articles Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow‐derived macrophages from Park2(−/−) and Pink1(−/−) mice. The caspase 1‐dependent release of IL‐1β and IL‐18 was, therefore, enhanced in Park2(−/−) and Pink1(−/−) cells. This defect was confirmed in blood‐derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin‐deficient cells was accompanied by a lack of induction of A20, a well‐known negative regulator of the NF‐κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL‐1β release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3‐inflammasome axis participates in the pathogenesis of PARK2‐linked PD, paving the way for the exploration of its potential as a biomarker and treatment target. John Wiley and Sons Inc. 2018-04-17 2018-08 /pmc/articles/PMC6190839/ /pubmed/29665074 http://dx.doi.org/10.1002/glia.23337 Text en © 2018 The Authors. Glia Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Articles Mouton‐Liger, François Rosazza, Thibault Sepulveda‐Diaz, Julia Ieang, Amélie Hassoun, Sidi‐Mohamed Claire, Emilie Mangone, Graziella Brice, Alexis Michel, Patrick P. Corvol, Jean‐Christophe Corti, Olga Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop |
title |
Parkin deficiency modulates
NLRP3 inflammasome activation
by attenuating an A20‐dependent
negative feedback loop |
title_full |
Parkin deficiency modulates
NLRP3 inflammasome activation
by attenuating an A20‐dependent
negative feedback loop |
title_fullStr |
Parkin deficiency modulates
NLRP3 inflammasome activation
by attenuating an A20‐dependent
negative feedback loop |
title_full_unstemmed |
Parkin deficiency modulates
NLRP3 inflammasome activation
by attenuating an A20‐dependent
negative feedback loop |
title_short |
Parkin deficiency modulates
NLRP3 inflammasome activation
by attenuating an A20‐dependent
negative feedback loop |
title_sort | parkin deficiency modulates
nlrp3 inflammasome activation
by attenuating an a20‐dependent
negative feedback loop |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190839/ https://www.ncbi.nlm.nih.gov/pubmed/29665074 http://dx.doi.org/10.1002/glia.23337 |
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