Browsing by Subject "complement"
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Item Blood Inflammatory Exosomes with Age Prime Microglia through Complement Signaling for Negative Stroke Outcomes(2020-05) Zhang, Hongxia; Jin, Kunlin; Forster, Michael J.; Yang, Shaohua; Shi, Xiangrong; Cunningham, J. ThomasThe systemic inflammatory milieu plays an important role in the age-related decline of functional integrity, but its contribution to age-related disease (e.g., stroke) remains largely unknown. Here, we found that activated complement molecules (C1q, C3a, C3b) in serum exosomes increased with age, whereas CD46, a C3b/C4b-inactivating factor, was higher in serum exosomes from young rats. These serum inflammatory exosomes passed the blood-brain barrier and primed the microglial response that led to exacerbation of synaptic loss and motor deficits after ischemic stroke via microglial C3a receptor (C3aR). When aged rats were exposed to serum exosomes from young rats, microglia-mediated synaptic loss was reduced and motor deficits after stroke were improved. Administration of C3aR inhibitor or microglial depletion attenuated synaptic loss associated with the treatment of serum exosome from aged rats, in parallel with improved post-stroke outcome. Our data suggest that peripheral circulating old exosomes act as inflammatory mediators and influence ischemic stroke outcome through a complement-microglia axis.Item Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion(Ivyspring International Publisher, 2020-01-01) 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-YuanMicroglial 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.