Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan.
Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
Ann Neurol. 2022 Apr;91(4):532-547. doi: 10.1002/ana.26327. Epub 2022 Mar 8.
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).
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.
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.
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.
repulsive guidance molecule-a（RGMa）是一种糖基磷脂酰肌醇连接的糖蛋白，具有多种功能，包括轴突生长抑制和免疫调节。然而，其在视神经脊髓炎（NMO）病理生理学中的作用知之甚少。血管周星形胶质细胞病是由水通道蛋白-4（AQP4）特异性 IgG 漏入中枢神经系统实质引起的，是 NMO 病理的一个关键特征。我们研究了 RGMa 在 NMO 星形胶质细胞病病理中的作用，并测试了人源化抗 RGMa 单克隆抗体（RGMa-mAb）的治疗潜力。
使用一种临床相关的 NMO 大鼠模型，我们通过行为测试、免疫组织化学和基因表达分析评估了 RGMa-mAb 的治疗效果。我们进一步进行了体外实验，以解决巨噬细胞中的 RGMa 信号。
在 NMO 大鼠和 NMO 尸检样本中，RGMa 由未受损的神经元和星形胶质细胞表达，而其受体 neogenin 由浸润的巨噬细胞表达。RGMa-mAb 治疗改善了 NMO 大鼠的 AQP4-IgG 诱导的星形胶质细胞病和临床恶化。RGMa-mAb 治疗显著抑制中性粒细胞浸润，并降低中性粒细胞趋化因子的表达。有趣的是，在病变中积累的表达 neogenin 的巨噬细胞表达 CXCL2，这是一种强烈的中性粒细胞趋化因子，进一步的分析表明，RGMa 直接调节巨噬细胞中的 CXCL2 表达。最后，我们发现我们的 NMO 大鼠发生了神经病理性疼痛，而 RGMa-mAb 治疗有效地改善了神经病理性疼痛的严重程度。
浸润巨噬细胞中的 RGMa 信号是 NMO 病变中与中性粒细胞相关的星形胶质细胞病的关键驱动因素，RGMa-mAb 可能为 NMO 相关的神经病理性疼痛和 NMO 患者的运动障碍提供有效的治疗策略。ANN NEUROL 2022；91：532-547。
