That Wasn't a Complement-Too Much C3 in Demyelinating Disease

Abstract

Multiple sclerosis is a chronic inflammatory disease characterized by demyelination in the central nervous system. In this issue of Immunity, Werneberg et al. report a striking loss of synapses driven by excessive microglial pruning early in demyelinating disease, which can be rescued by inhibiting the complement component C3.

Figure 1.. Viral Overexpression of the Complement C3 Inhibitor Crry Protects against Microglia-Mediated Synapse Loss in a Mouse Model of Demyelinating Disease

In experimental autoimmune encephalomyelitis (EAE), T cells attack the myelin sheath, leading to reactive gliosis and demyelination. Werneburg et al. (2020) show that in the early stages of EAE progression, the complement component C3 is highly localized to presynaptic terminals of retinal ganglion neurons in the visual thalamus. The upregulation of C3 is accompanied by increased microglial synapse pruning, decreased synapse density, and impaired visual acuity. Viral overexpression of the C3 inhibitor Crry in retinal ganglion neurons reduces C3 deposition on their synaptic terminals in the thalamus, decreases microglial synapse pruning, and partially rescues EAE-induced loss of synapses and visual acuity. Thus, complement C3 inhibition may be a viable therapeutic strategy in demyelinating disease.