中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (8): 3870-3880.doi: 10.4103/NRR.NRR-D-24-00898

• 原著:视神经损伤修复保护与再生 • 上一篇    

特异性视神经脊髓炎谱系疾病相关性视神经炎动物模型优化及其病理和功能动态特征

  

  • 出版日期:2026-08-18 发布日期:2026-04-28

Dynamic characterization of pathological and functional deterioration in a mouse model of optic neuritis related to neuromyelitis optica spectrum disorder

Xiayin Yang1, 2, Shi-Qi Yao1, Henry Ho-Lung Chan1, 3, 4, 5, 6, Shaoying Tan1, 3, 4, *   

  1. 1School of Optometry, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China; 
    2Department of Ophthalmology, The First Affiliated Hospital of the Medical College of Shantou University, Shantou, Guangdong Province, China; 
    3Research Center for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Kowloon, Hong Kong Special Administrative Region, China; 
    4Center for Eye and Vision Research (CEVR), 17W Hong Kong Science Park, Hong Kong Special Administrative Region, China; 
    5Research Center for Chinese Medicine Innovation (RCMI), The Hong Kong Polytechnic University, Kowloon, Hong Kong Special Administrative Region, China; 
    6University Research Facilities in Behavioral and Systems Neuroscience (UBSN), The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China
  • Online:2026-08-18 Published:2026-04-28
  • Contact: Shaoying Tan, PhD, shaoying.tan@polyu.edu.hk.
  • Supported by:
    The study was partially supported by the General Research Fund (GRF) from the Research Grants Council (RGC) of the Hong Kong Special Administrative Region, China, No. 15103522 (to ST); the Internal Research Grant from the Hong Kong Polytechnic University 2021-23, No. P0035512 (to ST) and  P0035375 (to HHLC); the Innovation and Technology Commission of the Hong Kong Special Administrative Region (ITC InnoHK CEVR Project); and The Hong Kong Polytechnics University Research Center for Sharp Vision, No. P0039595.

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摘要：

视神经脊髓炎谱系疾病相关性视神经炎（NMOSD-ON）涉及炎症和变性中多种细胞反应。然而，既往针对视神经脊髓炎谱系疾病机制的研究多数通过脊髓或颅脑动物模型实现，尤其需要提前激发动物的全身免疫反应，更无法清晰描绘特异性抗体独立引发的免疫反应过程。因此，构建由特异性抗体引发的针对性的视神经炎动物模型有助于深入探索视神经脊髓炎谱系疾病相关性视神经炎的机制，为此，实验通过将水通道蛋白4的特异性抗体精准地注射至小鼠视神经后段，诱发特异性的视神经炎症反应，从而获得了更具代表性的视神经脊髓炎谱系疾病相关性视神经炎小鼠模型。随后从组织学和功能上动态观察了炎症诱导后1个月内疾病的发展过程。结果发现，第1周内星形胶质细胞即被破坏，其特征包括水通道蛋白4和胶质纤维酸性蛋白丢失、小胶质细胞活化以及小胶质细胞相关细胞因子（肿瘤坏死因子、白细胞介素6、白细胞中介素1β、C-X-C基序趋化因子配体10和脑源性神经营养因子）上调。从第2周开始，视神经脱髓鞘的迹象以及轴突纤维和视神经节细胞体受损明显。视觉诱发电位和暗适应阈值正波反应均显示视觉通路和视网膜功能障碍；光学相干断层扫描显示，活体小鼠的视网膜神经纤维层变薄。综上，该研究动态描绘了特异性抗体所引发的视神经脊髓炎谱系疾病相关性视神经炎的发生发展过程，揭示了各阶段病理变化，并将组织学和分子学变化与活体结构和功能退化相关联。研究为视神经脊髓炎谱系疾病相关性视神经炎的进一步研究奠定了重要基础。


https://orcid.org/0000-0001-9997-7396 (Shaoying Tan)

关键词: 视神经炎, 视神经脊髓炎谱系疾病相关性视神经炎, 动物模型, 水通道蛋白4特异性抗体, 动态剖面, 病理学, 功能退化, 视觉诱发电位, 视网膜电图, 体内视网膜结构扫描

Abstract:

Neuromyelitis optica spectrum disorder–related optic neuritis involves various cellular responses to inflammation and degeneration. In most patients, the primary mechanism underlying neuromyelitis optica spectrum disorder–related optic neuritis is the interaction of aquaporin-4 antibodies with the aquaporin-4 protein present on astrocytes within posterior optic nerve. This binding subsequently initiates a cascade of events leading to secondary demyelination of the optic nerve, ultimately culminating in optic nerve degeneration. Earlier studies on this disorder primarily used systemic-induced animal models, which often require prior activation of a systemic immune response. This can result in primary demyelination of the optic nerve, complicating the interpretation of experimental results. Such methodologies hinder the ability to isolate immune responses triggered by specific antibodies. Additionally, the lack of a detailed profile of disease progression over time limits our capacity to identify potential intervention windows. Therefore, constructing a targeted optic neuritis animal model induced by specific antibodies and elucidate the disease progression arecrucial for exploring the mechanisms underlying neuromyelitis optica spectrum disorder– related optic neuritis. In this study, specific antibodies against aquaporin-4 were precisely injected into the retrobulbar optic nerve of mice to induce a targeted inflammatory response in the posterior optic nerve, resulting in a more representative mouse model of neuromyelitis optica spectrum disorder–related optic neuritis than current models. The progression of the disease was then dynamically observed from both histological and functional perspectives over the course of 1 month following the induction of inflammation. By the first week, astrocytes were damaged, as evidenced by the loss of aquaporin-4 and glial fibrillary acidic protein, the activation of microglia, and the upregulation of microglia-related cytokines, including tumor necrosis factor, interleukin-6, interleukin-1β, C–X–C motif ligand 10, and brain-derived neurotrophic factor. Starting from the second week, there were signs of optic nerve demyelination and significant damage to axonal fibers and retinal ganglion cell bodies. Visual-evoked potentials and dark adaptation threshold responses in electroretinogram both indicated dysfunction in the visual pathway and retina, while optical coherence tomography revealed thinning of the retinal nerve fiber layer in live mice. In summary, in this study we conducted a dynamic exploration of the occurrence and progression of neuromyelitis optica spectrum disorder–related optic neuritis triggered by specific antibodies. Our results show pathological changes at various stages and correlate histological and molecular alterations with in vivo structural and functional deterioration. The findings from this study lay an important foundation for further research on neuromyelitis optica spectrum disorder–related optic neuritis.

Key words: animal model, aquaporin-4 immunoglobulin G, dynamic profile, electroretinogram, functional deterioration, in vivo retinal structural scan, neuromyelitis optica spectrum disorder–related optic neuritis, optic neuritis, pathology, visual-evoked potential