Neutrophil-microglia interaction drives motor dysfunction in neuromyelitis optica model induced by subarachnoid AQP4-IgG - PubMed
3 months ago
- #Neuromyelitis optica
- #Autoimmunity
- #Neuroscience
- Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 water (AQP4) channels.
- A mouse NMO model was used to investigate molecular-cellular events preceding classical complement cascade activation by continuously infusing a non-complement-activating mouse monoclonal AQP4-IgG via spinal subarachnoid route.
- Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment, but no blood-brain barrier leakage.
- Motor impairment and neuronal dysfunction reversed when AQP4-IgG infusion stopped.
- Two-photon microscopy and electron-microscopy-based reconstructions revealed physical interaction of infiltrating neutrophils with microglia.
- Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles.
- Mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid-droplet burden and motor impairment.
- Pharmacological inhibition of C5aR1 recapitulated this protection.
- Immunohistochemical analysis of an NMO patient's spinal cord revealed disease-associated microglia surrounding motor neurons in non-destructive lesions.
- The study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.