Neutrophil-Microglia Interaction Drives Motor Dysfunction in a Neuromyelitis Optica Model Induced by Subarachnoid AQP4-IgG

Authors

Fangfang Qi
Vanda A Lennon
Shunyi Zhao
Yong Guo
Husheng Ding
Caiyun Liu
Whitney M Bartley
Tingjun Chen
Claudia F Lucchinetti
Long-Jun Wu

Language

English

Publication Date

4-1-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI199706

PMID

41665955

PMCID

PMC13038209

PubMedCentral® Posted Date

2-10-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 (AQP4) water channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. 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 both 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. Of note, 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 nondestructive lesions. Our 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.

Keywords

Animals, Mice, Aquaporin 4, Microglia, Neutrophils, Neuromyelitis Optica, Receptor, Anaphylatoxin C5a, Disease Models, Animal, Immunoglobulin G, Humans, Mice, Knockout, Female, Extracellular Traps, Complement C5a

Published Open-Access

yes

Recommended Citation

Qi, Fangfang; Lennon, Vanda A; Zhao, Shunyi; et al., "Neutrophil-Microglia Interaction Drives Motor Dysfunction in a Neuromyelitis Optica Model Induced by Subarachnoid AQP4-IgG" (2026). Faculty, Staff and Student Publications. 6810.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6810