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Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion

Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sp...

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Autores principales: Zhang, Lin-Yuan, Pan, Jiaji, Mamtilahun, Muyassar, Zhu, Yuan, Wang, Liping, Venkatesh, Ashwin, Shi, Rubing, Tu, Xuanqiang, Jin, Kunlin, Wang, Yongting, Zhang, Zhijun, Yang, Guo-Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929610/
https://www.ncbi.nlm.nih.gov/pubmed/31903107
http://dx.doi.org/10.7150/thno.35841
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author Zhang, Lin-Yuan
Pan, Jiaji
Mamtilahun, Muyassar
Zhu, Yuan
Wang, Liping
Venkatesh, Ashwin
Shi, Rubing
Tu, Xuanqiang
Jin, Kunlin
Wang, Yongting
Zhang, Zhijun
Yang, Guo-Yuan
author_facet Zhang, Lin-Yuan
Pan, Jiaji
Mamtilahun, Muyassar
Zhu, Yuan
Wang, Liping
Venkatesh, Ashwin
Shi, Rubing
Tu, Xuanqiang
Jin, Kunlin
Wang, Yongting
Zhang, Zhijun
Yang, Guo-Yuan
author_sort Zhang, Lin-Yuan
collection PubMed
description Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. Results: Cerebral vessel density and blood flow were reduced after hypoperfusion (p<0.05). Spatial learning and memory deficits and white matter injury were shown (p<0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (p<0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (p<0.05). Genetic deletion of C3ar1 significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (p<0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (p<0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (p<0.05). Conclusions: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia.
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spelling pubmed-69296102020-01-04 Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion Zhang, Lin-Yuan Pan, Jiaji Mamtilahun, Muyassar Zhu, Yuan Wang, Liping Venkatesh, Ashwin Shi, Rubing Tu, Xuanqiang Jin, Kunlin Wang, Yongting Zhang, Zhijun Yang, Guo-Yuan Theranostics Research Paper Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. Results: Cerebral vessel density and blood flow were reduced after hypoperfusion (p<0.05). Spatial learning and memory deficits and white matter injury were shown (p<0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (p<0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (p<0.05). Genetic deletion of C3ar1 significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (p<0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (p<0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (p<0.05). Conclusions: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia. Ivyspring International Publisher 2020-01-01 /pmc/articles/PMC6929610/ /pubmed/31903107 http://dx.doi.org/10.7150/thno.35841 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zhang, Lin-Yuan
Pan, Jiaji
Mamtilahun, Muyassar
Zhu, Yuan
Wang, Liping
Venkatesh, Ashwin
Shi, Rubing
Tu, Xuanqiang
Jin, Kunlin
Wang, Yongting
Zhang, Zhijun
Yang, Guo-Yuan
Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
title Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
title_full Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
title_fullStr Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
title_full_unstemmed Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
title_short Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
title_sort microglia exacerbate white matter injury via complement c3/c3ar pathway after hypoperfusion
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929610/
https://www.ncbi.nlm.nih.gov/pubmed/31903107
http://dx.doi.org/10.7150/thno.35841
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