| The complement system is implicated in a variety of neuroinflammatory disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Huntington's disease, and stroke. Within the CNS, resident cells are capable of generating complement activation components, regulatory proteins, and receptors, thus facilitating local inflammatory responses in the brain and spinal cord. The relative contribution to neuroinflammation facilitated by the complement anaphylatoxin C3a is largely unexplored. Previous studies have shown that the C3aR is up-regulated in the CNS during both chronic and acute inflammation, suggesting that C3a plays an important role in a variety of CNS insults. We hypothesized that C3a is a key mediator of chronic and acute CNS inflammation and utilized several animal models of neuroinflammation to address this forecast. We generated and characterized mice that express C3a exclusively in the CNS using the astrocyte-specific promoter glial fibrillary acidic protein (GFAP; C3a/GFAP mice) and acquired C3aR-deficient (C3aR-/-) mice to address the specific role C3a plays in the chronic model of CNS inflammation, experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). We also used these same animals and conducted studies using an acute model of inflammation, LPS-induced endotoxin shock, the animal model for septic shock. In both cases, C3a/GFAP mice showed a significantly different disease course than controls did. In EAE, C3a/GFAP mice showed exacerbated clinical features of disease, and this manifestation was accompanied by massive cellular infiltration of CD4+ T cells into the spinal cords of these animals. In contrast, C3a/GFAP mice showed significant attenuation of LPS-induced mortality compared to controls. Taken together, these data indicate that C3a not only plays a considerable role in proinflammatory immune responses but also can contribute significantly to anti-inflammatory effects in the CNS, depending on disease state. |
