Pathogenic role of CD169+ macrophages in neuronal loss and motor decline in NMO mice

Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disease characterized by debilitating symptoms, such as blindness or paralysis, often following a single acute attack. However, effective acute treatments to prevent long-term sequelae are currently limited. This study aimed to investigate the role of CD169-expressing macrophages during the acute phase of NMO. We developed an NMO mouse model by injecting high-affinity AQP4-IgG with human complement into the striatum, inducing NMO-like lesions marked by astrocyte loss and infiltration of microglia/macrophages and neutrophils. Immunohistochemical analyses revealed that CD169-expressing macrophages were the predominant infiltrating cells within the lesion core. Based on this finding, we explored the therapeutic potential of blocking CD169 function to mitigate NMO. CD169+ macrophages were activated by astrocytopathy, partially through SYK signaling, leading to significant neuronal loss and motor deficits. Treatment with an anti-CD169 antibody significantly reduced neuronal loss, improved motor function, and inhibited the phagocytic activity of CD169+ macrophages. Our findings demonstrate that CD169-expressing macrophages play a critical role in exacerbating tissue damage and functional decline during the acute phase of NMO. Targeting CD169 signaling may represent a promising therapeutic strategy to reduce pathological phagocytosis and prevent secondary injury in NMO.