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However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin\u20104 (AQP4)\u2010specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti\u2010RGMa monoclonal antibody (RGMa\u2010mAb).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa\u2010mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa\u2010signaling in macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In both NMO rats and an NMO\u2010autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4\u2010IgG\u2010induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa\u2010mAb treatment. RGMa\u2010mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin\u2010expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa\u2010mAb treatment effectively ameliorated the severity of neuropathic pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>RGMa signaling in infiltrated macrophages is a critical driver of neutrophil\u2010related astrocytopathy in NMO lesions, and RGMa\u2010mAb may provide an efficient therapeutic strategy for NMO\u2010associated neuropathic pain and motor deficits in patients with NMO. 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