Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation

Complement component C3 mediates pathology in several CNS neurodegenerative diseases, but the cellular and molecular mechanisms leading to neuronal injury remain unclear. We examined how C3 deletion affects glial profiles and anterior visual pathway pathology in an animal model of neuroinflammation, EAE. scRNA-seq from mouse brain and optic nerve revealed that C3 expression defined disease-associated glial subtypes characterized by increased expression of genes associated with mTOR activation, cell metabolism, and translation. This was confirmed with proteomic analysis of the optic nerves of C3KO and WT EAE mice. Deletion of C3 restored glia towards homeostatic profiles. Myeloid-derived C3 mediated injury in optic nerve axons and retinal ganglion cells (RGCs) at disease peak. Our study supports a direct role for C3 in activating the mTOR-ribosomal biogenesis axis in glia which subsequently mediate early neuro-axonal stress and synapse loss.