Fig. 2

Complement contributions to neuronal health, synaptic turnover, and self-perpetuating feed-forward inflammation and neuronal dysfunction in the CNS. (A) C1q synthesis is rapidly induced upon perturbation. C1q engagement with neurons after neuronal insult in the absence of the proteases C1r and C1s, promotes neuronal resilience. (B) As additional injury occurs, additional complement components C1r, C1s, C4, C2, and C3 are synthesized resulting in the formation of C1 complex, C1q, C1r₂, and C1s₂, and cleavage of C3 to C3b/iC3b, which promotes synaptic pruning by microglia via the CR3 receptor. (C) Further insults promote inflammation and complement activation. Once C3 is cleaved, if C5 is present, C5a is produced along with C3b and C3a. Inflammatory damage-associated microglia (DAM1) and damage-associated astrocytes (DAA) [141] are induced and promote neurotoxicity resulting in functional loss of neurons and eventual neuronal death. Neuronal death and/or overwhelmed clearance mechanisms further promote inflammation to continue the cycle of injury. DAAs and DAMs interact with DAMPS/PAMPS and complement C5a and C3a to perpetuate neurotoxicity