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α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia
Synucleinopathies such as Parkinson's disease (PD) are hallmarked by α‐synuclein (α‐syn) pathology and neuroinflammation. This neuroinflammation involves activated microglia with increased secretion of interleukin‐1β (IL‐1β). The main driver of IL‐1β secretion from microglia is the NLRP3 inflam...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247862/ https://www.ncbi.nlm.nih.gov/pubmed/33506583 http://dx.doi.org/10.1002/glia.23970 |
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author | Pike, Adrianne F. Varanita, Tatiana Herrebout, Maaike A. C. Plug, Bonnie C. Kole, Jeroen Musters, René J. P. Teunissen, Charlotte E. Hoozemans, Jeroen J. M. Bubacco, Luigi Veerhuis, Robert |
author_facet | Pike, Adrianne F. Varanita, Tatiana Herrebout, Maaike A. C. Plug, Bonnie C. Kole, Jeroen Musters, René J. P. Teunissen, Charlotte E. Hoozemans, Jeroen J. M. Bubacco, Luigi Veerhuis, Robert |
author_sort | Pike, Adrianne F. |
collection | PubMed |
description | Synucleinopathies such as Parkinson's disease (PD) are hallmarked by α‐synuclein (α‐syn) pathology and neuroinflammation. This neuroinflammation involves activated microglia with increased secretion of interleukin‐1β (IL‐1β). The main driver of IL‐1β secretion from microglia is the NLRP3 inflammasome. A critical link between microglial NLRP3 inflammasome activation and the progression of both α‐syn pathology and dopaminergic neurodegeneration has been identified in various PD models in vivo. α‐Syn is known to activate the microglial NLRP3 inflammasome in murine models, but its relationship to this inflammasome in human microglia has not been established. In this study, IL‐1β secretion from primary mouse microglia induced by α‐syn fibrils was dependent on NLRP3 inflammasome assembly and caspase‐1 activity, as previously reported. We show that exposure of primary human microglia to α‐syn fibrils also resulted in significant IL‐1β secretion that was dependent on inflammasome assembly and involved the recruitment of caspase‐1 protein to inflammasome scaffolds as visualized with superresolution microscopy. While canonical IL‐1β secretion was clearly dependent on caspase‐1 enzymatic activity, this activity was less clearly involved for α‐syn‐induced IL‐1β secretion from human microglia. This work presents similarities between primary human and mouse microglia in the mechanisms of activation of the NLRP3 inflammasome by α‐syn, but also highlights evidence to suggest that there may be a difference in the requirement for caspase‐1 activity in IL‐1β output. The data represent a novel characterization of PD‐related NLRP3 inflammasome activation in primary human microglia and further implicate this mechanism in the pathology underlying PD. |
format | Online Article Text |
id | pubmed-8247862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82478622021-07-02 α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia Pike, Adrianne F. Varanita, Tatiana Herrebout, Maaike A. C. Plug, Bonnie C. Kole, Jeroen Musters, René J. P. Teunissen, Charlotte E. Hoozemans, Jeroen J. M. Bubacco, Luigi Veerhuis, Robert Glia Research Articles Synucleinopathies such as Parkinson's disease (PD) are hallmarked by α‐synuclein (α‐syn) pathology and neuroinflammation. This neuroinflammation involves activated microglia with increased secretion of interleukin‐1β (IL‐1β). The main driver of IL‐1β secretion from microglia is the NLRP3 inflammasome. A critical link between microglial NLRP3 inflammasome activation and the progression of both α‐syn pathology and dopaminergic neurodegeneration has been identified in various PD models in vivo. α‐Syn is known to activate the microglial NLRP3 inflammasome in murine models, but its relationship to this inflammasome in human microglia has not been established. In this study, IL‐1β secretion from primary mouse microglia induced by α‐syn fibrils was dependent on NLRP3 inflammasome assembly and caspase‐1 activity, as previously reported. We show that exposure of primary human microglia to α‐syn fibrils also resulted in significant IL‐1β secretion that was dependent on inflammasome assembly and involved the recruitment of caspase‐1 protein to inflammasome scaffolds as visualized with superresolution microscopy. While canonical IL‐1β secretion was clearly dependent on caspase‐1 enzymatic activity, this activity was less clearly involved for α‐syn‐induced IL‐1β secretion from human microglia. This work presents similarities between primary human and mouse microglia in the mechanisms of activation of the NLRP3 inflammasome by α‐syn, but also highlights evidence to suggest that there may be a difference in the requirement for caspase‐1 activity in IL‐1β output. The data represent a novel characterization of PD‐related NLRP3 inflammasome activation in primary human microglia and further implicate this mechanism in the pathology underlying PD. John Wiley & Sons, Inc. 2021-01-28 2021-06 /pmc/articles/PMC8247862/ /pubmed/33506583 http://dx.doi.org/10.1002/glia.23970 Text en © 2021 The Authors. Glia published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://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 Pike, Adrianne F. Varanita, Tatiana Herrebout, Maaike A. C. Plug, Bonnie C. Kole, Jeroen Musters, René J. P. Teunissen, Charlotte E. Hoozemans, Jeroen J. M. Bubacco, Luigi Veerhuis, Robert α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia |
title |
α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia |
title_full |
α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia |
title_fullStr |
α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia |
title_full_unstemmed |
α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia |
title_short |
α‐Synuclein evokes NLRP3 inflammasome‐mediated IL‐1β secretion from primary human microglia |
title_sort | α‐synuclein evokes nlrp3 inflammasome‐mediated il‐1β secretion from primary human microglia |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247862/ https://www.ncbi.nlm.nih.gov/pubmed/33506583 http://dx.doi.org/10.1002/glia.23970 |
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