Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong Province 510630, China.
Department of Medical Retina and Neuro-Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province 510060, China.
Mol Ther. 2023 Sep 6;31(9):2715-2733. doi: 10.1016/j.ymthe.2023.07.017. Epub 2023 Jul 22.
Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by transverse myelitis and optic neuritis. The pathogenic serum IgG antibody against the aquaporin-4 (AQP4) on astrocytes triggers the activation of the complement cascade, causing astrocyte injury, followed by oligodendrocyte injury, demyelination, and neuronal loss. Complement C3 is positioned as a central player that relays upstream initiation signals to activate downstream effectors, potentially stimulating and amplifying host immune and inflammatory responses. However, whether targeting the inhibition of C3 signaling could ameliorate tissue injury, locomotor defects, and visual impairments in NMO remains to be investigated. In this study, using the targeted C3 inhibitor CR2-Crry led to a significant decrease in complement deposition and demyelination in both slice cultures and focal intracerebral injection models. Moreover, the treatment downregulated the expression of inflammatory cytokines and improved motor dysfunction in a systemic NMO mouse model. Similarly, employing serotype 2/9 adeno-associated virus (AAV2/9) to induce permanent expression of CR2-Crry resulted in a reduction in visual dysfunction by attenuating NMO-like lesions. Our findings reveal the therapeutic value of inhibiting the complement C3 signaling pathway in NMO.
视神经脊髓炎（NMO）是一种中枢神经系统（CNS）自身免疫性炎症性疾病，其特征为横贯性脊髓炎和视神经炎。针对星形胶质细胞上水通道蛋白-4（AQP4）的致病性血清 IgG 抗体触发补体级联反应的激活，导致星形胶质细胞损伤，随后是少突胶质细胞损伤、脱髓鞘和神经元丢失。补体 C3 被定位为一个核心参与者，它将上游起始信号传递给下游效应物，可能刺激和放大宿主的免疫和炎症反应。然而，靶向抑制 C3 信号是否能改善 NMO 中的组织损伤、运动缺陷和视力障碍仍有待研究。在这项研究中，使用靶向 C3 抑制剂 CR2-Crry 导致切片培养和局灶性脑内注射模型中补体沉积和脱髓鞘显著减少。此外，该治疗方法下调了炎症细胞因子的表达，并改善了全身性 NMO 小鼠模型中的运动功能障碍。同样，利用血清型 2/9 腺相关病毒（AAV2/9）诱导 CR2-Crry 的永久性表达，通过减轻类似 NMO 的病变来减少视觉功能障碍。我们的研究结果揭示了抑制 NMO 中补体 C3 信号通路的治疗价值。
