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

Thomas Garton, Matthew D. Smith, Ajay Kesharwani, Marjan Gharagozloo, Sungtaek Oh, Chan-Hyun Na, Martina Absinta, Daniel S. Reich, Donald J. Zack and Peter A. Calabresi ()
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Thomas Garton: Johns Hopkins University School of Medicine
Matthew D. Smith: Johns Hopkins University School of Medicine
Ajay Kesharwani: Johns Hopkins University School of Medicine
Marjan Gharagozloo: Johns Hopkins University School of Medicine
Sungtaek Oh: Johns Hopkins University School of Medicine
Chan-Hyun Na: Johns Hopkins University School of Medicine
Martina Absinta: Johns Hopkins University School of Medicine
Daniel S. Reich: Johns Hopkins University School of Medicine
Donald J. Zack: Johns Hopkins University School of Medicine
Peter A. Calabresi: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Complement component C3 mediates pathology in CNS neurodegenerative diseases. Here we use scRNAseq of sorted C3-reporter positive cells from mouse brain and optic nerve to characterize C3 producing glia in experimental autoimmune encephalomyelitis (EAE), a model in which peripheral immune cells infiltrate the CNS, causing reactive gliosis and neuro-axonal pathology. We find that C3 expression in the early inflammatory stage of EAE defines disease-associated glial subtypes characterized by increased expression of genes associated with mTOR activation and cell metabolism. This pro-inflammatory subtype is abrogated with genetic C3 depletion, a finding confirmed with proteomic analyses. In addition, early optic nerve axonal injury and retinal ganglion cell oxidative stress, but not loss of post-synaptic density protein 95, are ameliorated by selective deletion of C3 in myeloid cells. These data suggest that in addition to C3b opsonization of post synaptic proteins leading to neuronal demise, C3 activation is a contributor to reactive glia in the optic nerve.

Date: 2025
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DOI: 10.1038/s41467-025-58708-3

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