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Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
Lin-Yuan Zhang1, Jiaji Pan1, Muyassar Mamtilahun1
1Department of Neurology, Ruijin Hospital School of Medicine, and Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Theranostics
|January 7, 2020
Summary
Activated microglia worsen white matter injury through the complement C3-C3aR pathway in chronic cerebral hypoperfusion. Blocking C3aR signaling reduces neuroinflammation and cognitive deficits, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Microglial activation is implicated in white matter injury following cerebral hypoperfusion.
- The precise mechanisms driving this microglial involvement remain incompletely understood.
- Chronic cerebral hypoperfusion can lead to significant neurological deficits and white matter damage.
Purpose of the Study:
- To investigate if activated microglia exacerbate white matter injury via the complement C3-C3aR pathway in chronic cerebral hypoperfusion.
- To elucidate the role of the C3-C3aR signaling cascade in microglial activation and subsequent white matter damage.
- To assess the therapeutic potential of targeting the C3aR pathway for neuroprotection.
Main Methods:
- Adult rats underwent chronic cerebral hypoperfusion via bilateral common carotid artery occlusion.
- Cerebral blood flow, vessel density, neurobehavioral functions, and white matter integrity were assessed.
- Microglial activation, complement C3, and C3aR expression were evaluated using immunohistochemistry and genetic knockout models (C3aR knockout mice) and pharmacological inhibition (C3aR antagonist SB290157).
Main Results:
- Chronic hypoperfusion reduced cerebral blood flow and vessel density, leading to cognitive deficits and white matter injury.
- Aberrant microglial activation, characterized by myelin phagocytosis, correlated with increased C3 and C3aR expression.
- Genetic deletion of C3aR and pharmacological blockade significantly attenuated microglial activation, white matter injury, and cognitive impairments.
Conclusions:
- Activated microglia exacerbate white matter injury through the C3-C3aR pathway during chronic cerebral hypoperfusion.
- The C3aR pathway is critical in mediating neuroinflammation and white matter damage driven by aberrant microglial activation.
- Targeting C3aR presents a novel therapeutic strategy for small vessel disease and vascular dementia.
