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Extracellular DJ-1 induces sterile inflammation in the ischemic brain
Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136727/ https://www.ncbi.nlm.nih.gov/pubmed/34014921 http://dx.doi.org/10.1371/journal.pbio.3000939 |
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author | Nakamura, Koutarou Sakai, Seiichiro Tsuyama, Jun Nakamura, Akari Otani, Kento Kurabayashi, Kumiko Yogiashi, Yoshiko Masai, Hisao Shichita, Takashi |
author_facet | Nakamura, Koutarou Sakai, Seiichiro Tsuyama, Jun Nakamura, Akari Otani, Kento Kurabayashi, Kumiko Yogiashi, Yoshiko Masai, Hisao Shichita, Takashi |
author_sort | Nakamura, Koutarou |
collection | PubMed |
description | Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow–derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-8136727 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-81367272021-06-02 Extracellular DJ-1 induces sterile inflammation in the ischemic brain Nakamura, Koutarou Sakai, Seiichiro Tsuyama, Jun Nakamura, Akari Otani, Kento Kurabayashi, Kumiko Yogiashi, Yoshiko Masai, Hisao Shichita, Takashi PLoS Biol Research Article Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow–derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases. Public Library of Science 2021-05-20 /pmc/articles/PMC8136727/ /pubmed/34014921 http://dx.doi.org/10.1371/journal.pbio.3000939 Text en © 2021 Nakamura et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Nakamura, Koutarou Sakai, Seiichiro Tsuyama, Jun Nakamura, Akari Otani, Kento Kurabayashi, Kumiko Yogiashi, Yoshiko Masai, Hisao Shichita, Takashi Extracellular DJ-1 induces sterile inflammation in the ischemic brain |
title | Extracellular DJ-1 induces sterile inflammation in the ischemic brain |
title_full | Extracellular DJ-1 induces sterile inflammation in the ischemic brain |
title_fullStr | Extracellular DJ-1 induces sterile inflammation in the ischemic brain |
title_full_unstemmed | Extracellular DJ-1 induces sterile inflammation in the ischemic brain |
title_short | Extracellular DJ-1 induces sterile inflammation in the ischemic brain |
title_sort | extracellular dj-1 induces sterile inflammation in the ischemic brain |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136727/ https://www.ncbi.nlm.nih.gov/pubmed/34014921 http://dx.doi.org/10.1371/journal.pbio.3000939 |
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