Cargando…
Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain
It has been reported that neutrophil extracellular traps (NETs) play important roles in non-infectious diseases. In ischemic stroke, neutrophils infiltrate damaged brain tissue soon after injury and aggravate inflammation. Using a rat permanent MCAO model, we showed citrullinated histone H3(+) (CitH...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556959/ https://www.ncbi.nlm.nih.gov/pubmed/31177989 http://dx.doi.org/10.1186/s40478-019-0747-x |
_version_ | 1783425395849166848 |
---|---|
author | Kim, Seung-Woo Lee, Hahnbie Lee, Hye-Kyung Kim, Il-Doo Lee, Ja-Kyeong |
author_facet | Kim, Seung-Woo Lee, Hahnbie Lee, Hye-Kyung Kim, Il-Doo Lee, Ja-Kyeong |
author_sort | Kim, Seung-Woo |
collection | PubMed |
description | It has been reported that neutrophil extracellular traps (NETs) play important roles in non-infectious diseases. In ischemic stroke, neutrophils infiltrate damaged brain tissue soon after injury and aggravate inflammation. Using a rat permanent MCAO model, we showed citrullinated histone H3(+) (CitH3, a marker of NETosis) induction in neutrophils in leptomeninges and in peripheral blood soon after MCAO. Entry of CitH3(+) cells occurred through leptomeninges after 6 h of MCAO and these cells were observed in cerebral cortex from 12 h and subsequently in striatum. It is interesting to note that CitH3(+) induction began in circulating neutrophils before they migrated to brain parenchyma and they were detected as intact or lysed form. High mobility group box 1 (HMGB1), a danger associated molecular pattern (DAMP) molecule, was accumulated massively in serum after permanent MCAO and plays a critical role in CitH3 inductions in neutrophils in brain parenchyma and in peripheral blood. Both the all-thiol and disulfide types of HMGB1 induced CitH3 via their specific receptors, CXCR4 and TLR4, respectively. Importantly, HMGB1 not only induced NETosis but was included as a part of the extruded NETs, and contribute to NETosis-mediated neuronal death. Therefore, it would appear a vicious cycle exists between neuronal cell death and NETosis and HMGB1 mediates detrimental effects exerted by this cycle. When NETosis was suppressed by a PAD inhibitor in MCAO animals, delayed immune cell infiltrations were markedly suppressed and damages in blood vessels were significantly mitigated. The study shows NETosis with the involvement of HMGB1 as a mediator in a vicious cycle aggravates inflammation and subsequent damage in the ischemic brain. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-019-0747-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6556959 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-65569592019-06-13 Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain Kim, Seung-Woo Lee, Hahnbie Lee, Hye-Kyung Kim, Il-Doo Lee, Ja-Kyeong Acta Neuropathol Commun Research It has been reported that neutrophil extracellular traps (NETs) play important roles in non-infectious diseases. In ischemic stroke, neutrophils infiltrate damaged brain tissue soon after injury and aggravate inflammation. Using a rat permanent MCAO model, we showed citrullinated histone H3(+) (CitH3, a marker of NETosis) induction in neutrophils in leptomeninges and in peripheral blood soon after MCAO. Entry of CitH3(+) cells occurred through leptomeninges after 6 h of MCAO and these cells were observed in cerebral cortex from 12 h and subsequently in striatum. It is interesting to note that CitH3(+) induction began in circulating neutrophils before they migrated to brain parenchyma and they were detected as intact or lysed form. High mobility group box 1 (HMGB1), a danger associated molecular pattern (DAMP) molecule, was accumulated massively in serum after permanent MCAO and plays a critical role in CitH3 inductions in neutrophils in brain parenchyma and in peripheral blood. Both the all-thiol and disulfide types of HMGB1 induced CitH3 via their specific receptors, CXCR4 and TLR4, respectively. Importantly, HMGB1 not only induced NETosis but was included as a part of the extruded NETs, and contribute to NETosis-mediated neuronal death. Therefore, it would appear a vicious cycle exists between neuronal cell death and NETosis and HMGB1 mediates detrimental effects exerted by this cycle. When NETosis was suppressed by a PAD inhibitor in MCAO animals, delayed immune cell infiltrations were markedly suppressed and damages in blood vessels were significantly mitigated. The study shows NETosis with the involvement of HMGB1 as a mediator in a vicious cycle aggravates inflammation and subsequent damage in the ischemic brain. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-019-0747-x) contains supplementary material, which is available to authorized users. BioMed Central 2019-06-10 /pmc/articles/PMC6556959/ /pubmed/31177989 http://dx.doi.org/10.1186/s40478-019-0747-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Kim, Seung-Woo Lee, Hahnbie Lee, Hye-Kyung Kim, Il-Doo Lee, Ja-Kyeong Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain |
title | Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain |
title_full | Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain |
title_fullStr | Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain |
title_full_unstemmed | Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain |
title_short | Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain |
title_sort | neutrophil extracellular trap induced by hmgb1 exacerbates damages in the ischemic brain |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556959/ https://www.ncbi.nlm.nih.gov/pubmed/31177989 http://dx.doi.org/10.1186/s40478-019-0747-x |
work_keys_str_mv | AT kimseungwoo neutrophilextracellulartrapinducedbyhmgb1exacerbatesdamagesintheischemicbrain AT leehahnbie neutrophilextracellulartrapinducedbyhmgb1exacerbatesdamagesintheischemicbrain AT leehyekyung neutrophilextracellulartrapinducedbyhmgb1exacerbatesdamagesintheischemicbrain AT kimildoo neutrophilextracellulartrapinducedbyhmgb1exacerbatesdamagesintheischemicbrain AT leejakyeong neutrophilextracellulartrapinducedbyhmgb1exacerbatesdamagesintheischemicbrain |