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

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dc.creatorZhang, Lin-Yuan
dc.creatorPan, Jiaji
dc.creatorMamtilahun, Muyassar
dc.creatorZhu, Yuan
dc.creatorWang, Liping
dc.creatorVenkatesh, Ashwin
dc.creatorShi, Rubing
dc.creatorTu, Xuanqiang
dc.creatorJin, Kunlin
dc.creatorWang, Yongting
dc.creatorZhang, Zhijun
dc.creatorYang, Guo-Yuan
dc.creator.orcid0000-0002-1336-348X (Jin, Kunlin)
dc.date.accessioned2022-09-09T14:08:42Z
dc.date.available2022-09-09T14:08:42Z
dc.date.issued2020-01-01
dc.description.abstractMicroglial 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.
dc.description.sponsorshipThis study was supported by grants from the National Natural Science Foundation of China (81771251, GYY; 81771244, ZJZ; 81801170,YHT; 81870921,YTW), the National Key Research and Development Program of China (2016YFC1300600), Scientific Research and Innovation Program of Shanghai Education Commission (2019-01-07-00-02-E00064, GYY), the K. C. Wong Education Foundation (GYY), Science and Technology Commission of Shanghai Municipality (17ZR1413600, ZJZ), Science and Technology Opening program of the Education Ministry of Henan Province (182106000061, XMC and GYY), and the Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018QNA16).
dc.identifier.citationZhang, L. Y., Pan, J., Mamtilahun, M., Zhu, Y., Wang, L., Venkatesh, A., Shi, R., Tu, X., Jin, K., Wang, Y., Zhang, Z., & Yang, G. Y. (2020). Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion. Theranostics, 10(1), 74-90. https://doi.org/10.7150/thno.35841
dc.identifier.issn1838-7640
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31704
dc.identifier.volume10
dc.publisherIvyspring International Publisher
dc.relation.urihttps://doi.org/10.7150/thno.35841
dc.rights.holder© The author(s).
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceTheranostics
dc.subjectchronic cerebral hypoperfusion
dc.subjectcomplement
dc.subjectinflammation
dc.subjectmicroglia
dc.subjectwhite matter injury
dc.subject.meshAnimals
dc.subject.meshBrain Injuries / metabolism
dc.subject.meshBrain Injuries / pathology
dc.subject.meshBrain Ischemia / metabolism
dc.subject.meshBrain Ischemia / pathology
dc.subject.meshComplement C3 / metabolism
dc.subject.meshComplement Pathway, Classical
dc.subject.meshInflammation / metabolism
dc.subject.meshInflammation / pathology
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Knockout
dc.subject.meshMicroglia / pathology
dc.subject.meshPerfusion
dc.subject.meshRats
dc.subject.meshRats, Sprague-Dawley
dc.subject.meshReceptors, G-Protein-Coupled / metabolism
dc.subject.meshWhite Matter / metabolism
dc.subject.meshWhite Matter / pathology
dc.titleMicroglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
dc.typeArticle
dc.type.materialtext

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