Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Nakamura, Koutarou, Sakai, Seiichiro, Tsuyama, Jun, Nakamura, Akari, Otani, Kento, Kurabayashi, Kumiko, Yogiashi, Yoshiko, Masai, Hisao, Shichita, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
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
_version_ 1783695486428905472
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
work_keys_str_mv AT nakamurakoutarou extracellulardj1inducessterileinflammationintheischemicbrain
AT sakaiseiichiro extracellulardj1inducessterileinflammationintheischemicbrain
AT tsuyamajun extracellulardj1inducessterileinflammationintheischemicbrain
AT nakamuraakari extracellulardj1inducessterileinflammationintheischemicbrain
AT otanikento extracellulardj1inducessterileinflammationintheischemicbrain
AT kurabayashikumiko extracellulardj1inducessterileinflammationintheischemicbrain
AT yogiashiyoshiko extracellulardj1inducessterileinflammationintheischemicbrain
AT masaihisao extracellulardj1inducessterileinflammationintheischemicbrain
AT shichitatakashi extracellulardj1inducessterileinflammationintheischemicbrain