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Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor

The microtubule-stabilizing drug epothilone B (epoB) has shown potential value in the treatment of spinal cord injury (SCI) through diverse mechanisms. However, it remains elusive why a limited overall effect was observed. We aim to investigate the limiting factors underlying functional recovery pro...

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Autores principales: Mao, Liang, Gao, Wei, Chen, Shurui, Song, Ying, Song, Changwei, Zhou, Zipeng, Zhao, Haosen, Zhou, Kang, Wang, Wei, Zhu, Kunming, Liu, Chang, Mei, Xifan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775408/
https://www.ncbi.nlm.nih.gov/pubmed/29095439
http://dx.doi.org/10.1038/cddis.2017.542
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author Mao, Liang
Gao, Wei
Chen, Shurui
Song, Ying
Song, Changwei
Zhou, Zipeng
Zhao, Haosen
Zhou, Kang
Wang, Wei
Zhu, Kunming
Liu, Chang
Mei, Xifan
author_facet Mao, Liang
Gao, Wei
Chen, Shurui
Song, Ying
Song, Changwei
Zhou, Zipeng
Zhao, Haosen
Zhou, Kang
Wang, Wei
Zhu, Kunming
Liu, Chang
Mei, Xifan
author_sort Mao, Liang
collection PubMed
description The microtubule-stabilizing drug epothilone B (epoB) has shown potential value in the treatment of spinal cord injury (SCI) through diverse mechanisms. However, it remains elusive why a limited overall effect was observed. We aim to investigate the limiting factors underlying functional recovery promoted by epoB. The same SCI model treated by epoB was established as discussed previously. We used a cerebrospinal fluid (CSF) sample to assess the changes in cytokines in milieu of the SCI lesion site after epoB treatment. We then analyzed the source of cytokines, the state of microglia/macrophages/monocytes (M/Ms), and the recruitment of neutrophil in the lesion site by using the results of antibody array. Following these findings, we further evaluated the motor functional recovery caused by the reshaped microenvironment. Systemic administration of epoB significantly increased levels of several cytokines in the CSF of the rat SCI model; macrophage colony-stimulating factor (M-CSF) secreted by intact central nervous system (CNS) cells was one of the cytokines with increased levels. Along with epoB and other cytokines, M-CSF reshapes the SCI milieu by activating the microglias, killing bone marrow-derived macrophages, polarizing the M/M to M1 phenotype, and activating downstream cytokines to exacerbate the SCI injury, but it also increases the expression of neurotrophic factors. Anti-inflammatory therapy using a neutralizing antibody mix shows encouraging results. Using in vivo experiments, our findings indicate that epoB inhibits the SCI functional recovery in many ways by reshaping the milieu, which counteracts the therapeutic efficacy that led to the limited overall effectiveness.
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spelling pubmed-57754082018-01-23 Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor Mao, Liang Gao, Wei Chen, Shurui Song, Ying Song, Changwei Zhou, Zipeng Zhao, Haosen Zhou, Kang Wang, Wei Zhu, Kunming Liu, Chang Mei, Xifan Cell Death Dis Original Article The microtubule-stabilizing drug epothilone B (epoB) has shown potential value in the treatment of spinal cord injury (SCI) through diverse mechanisms. However, it remains elusive why a limited overall effect was observed. We aim to investigate the limiting factors underlying functional recovery promoted by epoB. The same SCI model treated by epoB was established as discussed previously. We used a cerebrospinal fluid (CSF) sample to assess the changes in cytokines in milieu of the SCI lesion site after epoB treatment. We then analyzed the source of cytokines, the state of microglia/macrophages/monocytes (M/Ms), and the recruitment of neutrophil in the lesion site by using the results of antibody array. Following these findings, we further evaluated the motor functional recovery caused by the reshaped microenvironment. Systemic administration of epoB significantly increased levels of several cytokines in the CSF of the rat SCI model; macrophage colony-stimulating factor (M-CSF) secreted by intact central nervous system (CNS) cells was one of the cytokines with increased levels. Along with epoB and other cytokines, M-CSF reshapes the SCI milieu by activating the microglias, killing bone marrow-derived macrophages, polarizing the M/M to M1 phenotype, and activating downstream cytokines to exacerbate the SCI injury, but it also increases the expression of neurotrophic factors. Anti-inflammatory therapy using a neutralizing antibody mix shows encouraging results. Using in vivo experiments, our findings indicate that epoB inhibits the SCI functional recovery in many ways by reshaping the milieu, which counteracts the therapeutic efficacy that led to the limited overall effectiveness. Nature Publishing Group 2017-11 2017-11-02 /pmc/articles/PMC5775408/ /pubmed/29095439 http://dx.doi.org/10.1038/cddis.2017.542 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Mao, Liang
Gao, Wei
Chen, Shurui
Song, Ying
Song, Changwei
Zhou, Zipeng
Zhao, Haosen
Zhou, Kang
Wang, Wei
Zhu, Kunming
Liu, Chang
Mei, Xifan
Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
title Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
title_full Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
title_fullStr Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
title_full_unstemmed Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
title_short Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
title_sort epothilone b impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775408/
https://www.ncbi.nlm.nih.gov/pubmed/29095439
http://dx.doi.org/10.1038/cddis.2017.542
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