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Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease
Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either neurotoxic or neuroprotective effects in the immune pathogenesis of Parkinson’s disease (PD). Exploiting the beneficial properties of microglia cel...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852118/ https://www.ncbi.nlm.nih.gov/pubmed/29540778 http://dx.doi.org/10.1038/s41419-018-0437-9 |
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author | Du, Ren-Hong Sun, Hong-Bin Hu, Zhao-Li Lu, Ming Ding, Jian-Hua Hu, Gang |
author_facet | Du, Ren-Hong Sun, Hong-Bin Hu, Zhao-Li Lu, Ming Ding, Jian-Hua Hu, Gang |
author_sort | Du, Ren-Hong |
collection | PubMed |
description | Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either neurotoxic or neuroprotective effects in the immune pathogenesis of Parkinson’s disease (PD). Exploiting the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of PD. However, the mechanism that regulates microglia polarization remains elusive. Here we demonstrated that Kir6.1-containing ATP-sensitive potassium (Kir6.1/K-ATP) channel switched microglia from the detrimental M1 phenotype toward the beneficial M2 phenotype. Kir6.1 knockdown inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, while Kir6.1 overexpression promoted M2 polarization and synchronously alleviated the toxic phase of M1 microglia polarization. Furthermore, we observed that the Kir6.1 deficiency dramatically exacerbated dopaminergic neuron death companied by microglia activation in mouse model of PD. Mechanistically, Kir6.1 deficiency enhanced the activation of p38 MAPK–NF-κB pathway and increased the ratio of M1/M2 markers in the substantia nigra compacta of mouse model of PD. Suppression of p38 MAPK in vivo partially rescued the deleterious effects of Kir6.1 ablation on microglia phenotype and dopaminergic neuron death. Collectively, our findings reveal that Kir6.1/K-ATP channel modulates microglia phenotypes transition via inhibition of p38 MAPK–NF-κB signaling pathway and Kir6.1/K-ATP channel may be a promising therapeutic target for PD. |
format | Online Article Text |
id | pubmed-5852118 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58521182018-03-15 Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease Du, Ren-Hong Sun, Hong-Bin Hu, Zhao-Li Lu, Ming Ding, Jian-Hua Hu, Gang Cell Death Dis Article Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either neurotoxic or neuroprotective effects in the immune pathogenesis of Parkinson’s disease (PD). Exploiting the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of PD. However, the mechanism that regulates microglia polarization remains elusive. Here we demonstrated that Kir6.1-containing ATP-sensitive potassium (Kir6.1/K-ATP) channel switched microglia from the detrimental M1 phenotype toward the beneficial M2 phenotype. Kir6.1 knockdown inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, while Kir6.1 overexpression promoted M2 polarization and synchronously alleviated the toxic phase of M1 microglia polarization. Furthermore, we observed that the Kir6.1 deficiency dramatically exacerbated dopaminergic neuron death companied by microglia activation in mouse model of PD. Mechanistically, Kir6.1 deficiency enhanced the activation of p38 MAPK–NF-κB pathway and increased the ratio of M1/M2 markers in the substantia nigra compacta of mouse model of PD. Suppression of p38 MAPK in vivo partially rescued the deleterious effects of Kir6.1 ablation on microglia phenotype and dopaminergic neuron death. Collectively, our findings reveal that Kir6.1/K-ATP channel modulates microglia phenotypes transition via inhibition of p38 MAPK–NF-κB signaling pathway and Kir6.1/K-ATP channel may be a promising therapeutic target for PD. Nature Publishing Group UK 2018-03-14 /pmc/articles/PMC5852118/ /pubmed/29540778 http://dx.doi.org/10.1038/s41419-018-0437-9 Text en © The Author(s) 2018 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/. |
spellingShingle | Article Du, Ren-Hong Sun, Hong-Bin Hu, Zhao-Li Lu, Ming Ding, Jian-Hua Hu, Gang Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease |
title | Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease |
title_full | Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease |
title_fullStr | Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease |
title_full_unstemmed | Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease |
title_short | Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease |
title_sort | kir6.1/k-atp channel modulates microglia phenotypes: implication in parkinson’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852118/ https://www.ncbi.nlm.nih.gov/pubmed/29540778 http://dx.doi.org/10.1038/s41419-018-0437-9 |
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