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

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

2025
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Overview
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. Excessive complement C3 causes synaptic stripping and neurodegeneration. Here, the authors used the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and single-cell RNA sequencing to show that C3 expression defines disease-associated reactive glia. C3 deletion abrogated these pro-inflammatory glia and protected neurons.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject

13/1

/ 13/31

/ 13/51

/ 14/19

/ 14/32

/ 14/34

/ 14/63

/ 38/39

/ 59

/ 631/250/2501

/ 631/250/256/2516

/ 631/378/1689/1666

/ 692/617/375/1666

/ 692/699/375/364

/ Animals

/ Axons - metabolism

/ Axons - pathology

/ Brain - metabolism

/ Brain - pathology

/ Cell activation

/ Central Nervous System - pathology

/ Complement C3 - genetics

/ Complement C3 - immunology

/ Complement C3 - metabolism

/ Complement component C3

/ Deletion

/ Encephalomyelitis

/ Encephalomyelitis, Autoimmune, Experimental - immunology

/ Encephalomyelitis, Autoimmune, Experimental - metabolism

/ Encephalomyelitis, Autoimmune, Experimental - pathology

/ Experimental allergic encephalomyelitis

/ Female

/ Gene expression

/ Gene sequencing

/ Gliosis

/ Gliosis - immunology

/ Gliosis - metabolism

/ Gliosis - pathology

/ Humanities and Social Sciences

/ Immune system

/ Inflammation

/ Injury analysis

/ Mice

/ Mice, Inbred C57BL

/ Mice, Knockout

/ multidisciplinary

/ Multiple sclerosis

/ Myeloid cells

/ Myeloid Cells - immunology

/ Myeloid Cells - metabolism

/ Nerves

/ Neurodegenerative diseases

/ Neuroglia - metabolism

/ Neuronal-glial interactions

/ Neurons - metabolism

/ Neurons - pathology

/ Opsonization

/ Optic nerve

/ Optic Nerve - immunology

/ Optic Nerve - metabolism

/ Optic Nerve - pathology

/ Oxidative Stress

/ Pathology

/ Proteins

/ Proteomics

/ Retinal Ganglion Cells - metabolism

/ Retinal Ganglion Cells - pathology

/ Science

/ Science (multidisciplinary)

/ Synaptic density

/ TOR protein

/ Transcription activation