RGMa Signal in Macrophages Induces Neutrophil‐Related Astrocytopathy in NMO

Objective Repulsive guidance molecule‐a (RGMa) is a glycosylphosphatidylinositol‐linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin‐4 (AQP4)‐specific 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‐RGMa monoclonal antibody (RGMa‐mAb). Methods Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa‐mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa‐signaling in macrophages. Results In both NMO rats and an NMO‐autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4‐IgG‐induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa‐mAb treatment. RGMa‐mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin‐expressing 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‐mAb treatment effectively ameliorated the severity of neuropathic pain. Interpretation RGMa signaling in infiltrated macrophages is a critical driver of neutrophil‐related astrocytopathy in NMO lesions, and RGMa‐mAb may provide an efficient therapeutic strategy for NMO‐associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532–547