Gamma subunit of complement component 8 is an innate immune suppressor in brain

Abstract

Abstract The complement system is a part of the innate immune system, which comprises several small proteins activated by sequential cleavages. The majority of these complement components, such as components 3a (C3a) and C5a, are chemotactic and pro-inflammatory. However, in this study, we revealed an inhibitory role of complement component 8 gamma (C8G) in neuroinflammation. Novel findings show that the expression level of C8G increases in inflamed brain, and C8G is mainly localized to brain astrocytes. Experiments using recombinant C8G protein and shRNA-mediated knockdown showed that C8G inhibits microglial activation and neuroinflammation. In acute and chronic animal models of Alzheimer’s disease (AD), which exhibit strong neuroinflammation, C8G attenuated cognitive decline and glial hyperactivation. In these animals and patients with AD, we found higher C8G levels in brain tissue, cerebrospinal fluid, and plasma. Additionally, we identified sphingosine-1-phosphate receptor 2 (S1PR2) as a novel interaction protein of C8G and demonstrated that astrocyte-derived C8G interacts with S1PR2 to antagonize the pro-inflammatory action of S1P in microglia. Taken together, our results reveal a previously unrecognized role of C8G as a neuroinflammation inhibitor and indicate that C8G can be used therapeutically for the containment of neuroinflammation and treatment of related neurological diseases, such as AD.