Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging
Autor: | Jörg Köhl, Alexandra Litvinchuk, Ethan R. Roy, Hui Zheng, Nicholas E. Propson |
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Rok vydání: | 2021 |
Předmět: |
Vasculitis
0301 basic medicine Aging Capillary Permeability Mice 03 medical and health sciences 0302 clinical medicine Immune system Animals Aging brain Medicine Neuroinflammation Mice Knockout Innate immune system Microglia biology business.industry Neurodegeneration General Medicine medicine.disease Receptors Complement Cell biology Complement system 030104 developmental biology medicine.anatomical_structure Blood-Brain Barrier 030220 oncology & carcinogenesis Complement C3a Commentary biology.protein Endothelium Vascular C3a receptor business |
Zdroj: | J Clin Invest |
ISSN: | 1558-8238 0021-9738 |
Popis: | Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease. |
Databáze: | OpenAIRE |
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