Kim, Jong-Heon Afridi, Ruqayya Han, Jin Jung, Hyun-Gug Kim, Seung-Chan Hwang, Eun Mi Shim, Hyun Soo Ryu, Hoon Choe, Youngshik Hoe, Hyang-Sook Suk, Kyoungho 2024-01-19T15:32:24Z 2024-01-19T15:32:24Z 2021-09-02 2021-02 0006-8950 https://pubs.kist.re.kr/handle/201004/117482 The complement system is part of the innate immune system that 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. In patients with Alzheimer's disease, who exhibit strong neuroinflammation, we found higher C8G levels in brain tissue, CSF, and plasma. Our novel findings also showed that the expression level of C8G increases in the inflamed mouse brain, and that C8G is mainly localized to brain astrocytes. Experiments using recombinant C8G protein and shRNA-mediated knockdown showed that C8G inhibits glial hyperactivation, neuroinflammation, and cognitive decline in acute and chronic animal models of Alzheimer's disease. 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 the previously unrecognized role of C8G as a neuroinflammation inhibitor. Our findings pave the way towards therapeutic containment of neuroinflammation in Alzheimer's disease and related neurological diseases. English OXFORD UNIV PRESS Gamma subunit of complement component 8 is a neuroinflammation inhibitor Article 10.1093/brain/awaa425 1 BRAIN, v.144, no.2, pp.528 - 552 BRAIN 144 2 528 552 N scie scopus 000880372000030 2-s2.0-85102910776 Clinical Neurology Neurosciences Neurosciences & Neurology Article TNF-ALPHA SPHINGOSINE-1-PHOSPHATE RECEPTOR-2 ACTIVATION EXPRESSION MICROGLIA BRAIN NEURONS neuroinflammation astrocytes complement component 8 gamma microglia sphingosine-1-phosphate receptor 2