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Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia

BACKGROUND: Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the c...

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Autores principales: Cao, Qian, Chen, Jian, Zhang, Zhi, Shu, Shu, Qian, Yi, Yang, Lixuan, Xu, Lushan, Zhang, Yuxin, Bao, Xinyu, Xia, Shengnan, Yang, Haiyan, Xu, Yun, Qiu, Shuwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155379/
https://www.ncbi.nlm.nih.gov/pubmed/37138312
http://dx.doi.org/10.1186/s12974-023-02780-3
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author Cao, Qian
Chen, Jian
Zhang, Zhi
Shu, Shu
Qian, Yi
Yang, Lixuan
Xu, Lushan
Zhang, Yuxin
Bao, Xinyu
Xia, Shengnan
Yang, Haiyan
Xu, Yun
Qiu, Shuwei
author_facet Cao, Qian
Chen, Jian
Zhang, Zhi
Shu, Shu
Qian, Yi
Yang, Lixuan
Xu, Lushan
Zhang, Yuxin
Bao, Xinyu
Xia, Shengnan
Yang, Haiyan
Xu, Yun
Qiu, Shuwei
author_sort Cao, Qian
collection PubMed
description BACKGROUND: Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism. METHODS: Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7–10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry. RESULTS: CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2). CONCLUSION: Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02780-3.
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spelling pubmed-101553792023-05-04 Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia Cao, Qian Chen, Jian Zhang, Zhi Shu, Shu Qian, Yi Yang, Lixuan Xu, Lushan Zhang, Yuxin Bao, Xinyu Xia, Shengnan Yang, Haiyan Xu, Yun Qiu, Shuwei J Neuroinflammation Research BACKGROUND: Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism. METHODS: Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7–10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry. RESULTS: CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2). CONCLUSION: Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02780-3. BioMed Central 2023-05-03 /pmc/articles/PMC10155379/ /pubmed/37138312 http://dx.doi.org/10.1186/s12974-023-02780-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Cao, Qian
Chen, Jian
Zhang, Zhi
Shu, Shu
Qian, Yi
Yang, Lixuan
Xu, Lushan
Zhang, Yuxin
Bao, Xinyu
Xia, Shengnan
Yang, Haiyan
Xu, Yun
Qiu, Shuwei
Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
title Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
title_full Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
title_fullStr Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
title_full_unstemmed Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
title_short Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
title_sort astrocytic cxcl5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155379/
https://www.ncbi.nlm.nih.gov/pubmed/37138312
http://dx.doi.org/10.1186/s12974-023-02780-3
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