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

Abstract

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.

Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion

“…We further showed that microglial activation was secondary to C3aR signaling. Of note, previous studies have implicated complement alternative pathway-activated C3-C3aR signaling in demyelination (33) and neurodegeneration (34). In addition, C1q has been shown to induce axon damage in neurodegeneration (35), bind to a "receptor" in mitochondria (36), and induce neuronal stress (37).…”

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension

“…However, the neuroprotective microglial state (surveillance/execution mode) can be disturbed during pathology, causing these cells to shift toward a reactive phenotype. These reactive microglia respond with exacerbated secretion of proinflammatory mediators (Vinuesa et al, 2019) and altered phagocytotic properties (Baik et al, 2019;Zhang et al, 2020).…”

Acupuncture Improves White Matter Perfusion and Integrity in Rat Model of Vascular Dementia: An MRI-Based Imaging Study

“…Third, since this is an imaging study, we focused mainly on the macroscopic changes of brain and did not assume and detect signaling pathways mediating the white matter lesions and microglial activation. In fact, microglial polarization mediated inflammatory and complement pathways contribute to white matter lesions in the VaD model ( Qin et al, 2018 ; Zhang et al, 2020 ). Therefore, the downstream mechanism needs to be addressed in future studies as a next step to clarify the molecular target of acupuncture.…”

“…Due to the deep location at non-overlapping regions of cerebral arterioles or capillaries, white matter is vulnerable to the CBF reductions ( Wang et al, 2020 ). White matter lesions caused by ischemia, encompassing axonal damage, loss of myelin-associated glycoproteins, and microglial activation, are common pathological changes in VaD ( Struys et al, 2017 ; Qin et al, 2018 ; Zhang et al, 2020 ). Diffusion tensor imaging (DTI) study reports that VaD patients have a specific pattern of white matter lesions affecting the thalamic radiations or corpus callosum (CC) to a greater extent ( Fu et al, 2012 ; Palesi et al, 2018 ), which appears as decreased fractional anisotropy (FA), increased radial diffusivity (RD), and axial diffusivity (AD) ( Choi et al, 2016 ; Ben-Ari et al, 2019 ).…”