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ASK1 signaling regulates phase-specific glial interactions during neuroinflammation
Neuroinflammation is well known to be associated with neurodegenerative diseases. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been implicated in neuroinflammation, but its precise cellular and molecular mechanisms remain unknown. In this s...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832969/ https://www.ncbi.nlm.nih.gov/pubmed/35101972 http://dx.doi.org/10.1073/pnas.2103812119 |
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author | Guo, Xiaoli Kimura, Atsuko Namekata, Kazuhiko Harada, Chikako Arai, Nobutaka Takeda, Kohsuke Ichijo, Hidenori Harada, Takayuki |
author_facet | Guo, Xiaoli Kimura, Atsuko Namekata, Kazuhiko Harada, Chikako Arai, Nobutaka Takeda, Kohsuke Ichijo, Hidenori Harada, Takayuki |
author_sort | Guo, Xiaoli |
collection | PubMed |
description | Neuroinflammation is well known to be associated with neurodegenerative diseases. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been implicated in neuroinflammation, but its precise cellular and molecular mechanisms remain unknown. In this study, we generated conditional knockout (CKO) mice that lack ASK1 in T cells, dendritic cells, microglia/macrophages, microglia, or astrocytes, to assess the roles of ASK1 during experimental autoimmune encephalomyelitis (EAE). We found that neuroinflammation was reduced in both the early and later stages of EAE in microglia/macrophage-specific ASK1 knockout mice, whereas only the later-stage neuroinflammation was ameliorated in astrocyte-specific ASK1 knockout mice. ASK1 deficiency in T cells and dendritic cells had no significant effects on EAE severity. Further, we found that ASK1 in microglia/macrophages induces a proinflammatory environment, which subsequently activates astrocytes to exacerbate neuroinflammation. Microglia-specific ASK1 deletion was achieved using a CX3CR1(CreER) system, and we found that ASK1 signaling in microglia played a major role in generating and maintaining disease. Activated astrocytes produce key inflammatory mediators, including CCL2, that further activated and recruited microglia/macrophages, in an astrocytic ASK1-dependent manner. Astrocyte-specific analysis revealed CCL2 expression was higher in the later stage compared with the early stage, suggesting a greater proinflammatory role of astrocytes in the later stage. Our findings demonstrate cell-type–specific roles of ASK1 and suggest phase-specific ASK1-dependent glial cell interactions in EAE pathophysiology. We propose glial ASK1 as a promising therapeutic target for reducing neuroinflammation. |
format | Online Article Text |
id | pubmed-8832969 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-88329692022-07-31 ASK1 signaling regulates phase-specific glial interactions during neuroinflammation Guo, Xiaoli Kimura, Atsuko Namekata, Kazuhiko Harada, Chikako Arai, Nobutaka Takeda, Kohsuke Ichijo, Hidenori Harada, Takayuki Proc Natl Acad Sci U S A Biological Sciences Neuroinflammation is well known to be associated with neurodegenerative diseases. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been implicated in neuroinflammation, but its precise cellular and molecular mechanisms remain unknown. In this study, we generated conditional knockout (CKO) mice that lack ASK1 in T cells, dendritic cells, microglia/macrophages, microglia, or astrocytes, to assess the roles of ASK1 during experimental autoimmune encephalomyelitis (EAE). We found that neuroinflammation was reduced in both the early and later stages of EAE in microglia/macrophage-specific ASK1 knockout mice, whereas only the later-stage neuroinflammation was ameliorated in astrocyte-specific ASK1 knockout mice. ASK1 deficiency in T cells and dendritic cells had no significant effects on EAE severity. Further, we found that ASK1 in microglia/macrophages induces a proinflammatory environment, which subsequently activates astrocytes to exacerbate neuroinflammation. Microglia-specific ASK1 deletion was achieved using a CX3CR1(CreER) system, and we found that ASK1 signaling in microglia played a major role in generating and maintaining disease. Activated astrocytes produce key inflammatory mediators, including CCL2, that further activated and recruited microglia/macrophages, in an astrocytic ASK1-dependent manner. Astrocyte-specific analysis revealed CCL2 expression was higher in the later stage compared with the early stage, suggesting a greater proinflammatory role of astrocytes in the later stage. Our findings demonstrate cell-type–specific roles of ASK1 and suggest phase-specific ASK1-dependent glial cell interactions in EAE pathophysiology. We propose glial ASK1 as a promising therapeutic target for reducing neuroinflammation. National Academy of Sciences 2022-01-31 2022-02-08 /pmc/articles/PMC8832969/ /pubmed/35101972 http://dx.doi.org/10.1073/pnas.2103812119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Guo, Xiaoli Kimura, Atsuko Namekata, Kazuhiko Harada, Chikako Arai, Nobutaka Takeda, Kohsuke Ichijo, Hidenori Harada, Takayuki ASK1 signaling regulates phase-specific glial interactions during neuroinflammation |
title | ASK1 signaling regulates phase-specific glial interactions during neuroinflammation |
title_full | ASK1 signaling regulates phase-specific glial interactions during neuroinflammation |
title_fullStr | ASK1 signaling regulates phase-specific glial interactions during neuroinflammation |
title_full_unstemmed | ASK1 signaling regulates phase-specific glial interactions during neuroinflammation |
title_short | ASK1 signaling regulates phase-specific glial interactions during neuroinflammation |
title_sort | ask1 signaling regulates phase-specific glial interactions during neuroinflammation |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832969/ https://www.ncbi.nlm.nih.gov/pubmed/35101972 http://dx.doi.org/10.1073/pnas.2103812119 |
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