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.
Keywords: astrocytes; complement component 8 gamma; microglia; neuroinflammation;
sphingosine-1-phosphate receptor 2.
Reference
Kim, J. H., Afridi, R., Han, J., Jung, H. G., Kim, S. C., Hwang, E. M., ... & Suk, K. (2021). Gamma subunit of complement component 8 is a neuroinflammation inhibitor. Brain, 144(2), 528-552.