Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine, Munich, Germany.
Department of Neurology, Technical University of Munich School of Medicine, Munich, Germany.
J Mol Med (Berl). 2022 Jun;100(6):933-946. doi: 10.1007/s00109-022-02202-6. Epub 2022 May 10.
Aquaporin-4 (AQP4) is the molecular target of the immune response in neuromyelitis optica (NMO) that leads to severe structural damage in the central nervous system (CNS) and in the retina. Conversely, AQP4 might be upregulated in astrocytes as a compensatory event in multiple sclerosis. Thus, the functional relevance of AQP4 in neuroinflammation needs to be defined. Here, we tested the role of AQP4 in the retina in MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) using optical coherence tomography (OCT), OCT angiography, immunohistology, flow cytometry, and gene expression analysis in wild-type and Aqp4 mice. No direct infiltrates of inflammatory cells were detected in the retina. Yet, early retinal expression of TNF and Iba1 suggested that the retina participated in the inflammatory response during EAE in a similar way in wild-type and Aqp4 mice. While wild-type mice rapidly cleared retinal swelling, Aqp4 animals exhibited a sustainedly increased retinal thickness associated with retinal hyperperfusion, albumin extravasation, and upregulation of GFAP as a hallmark of retinal scarring at later stages of EAE. Eventually, the loss of retinal ganglion cells was higher in Aqp4 mice than in wild-type mice. Therefore, AQP4 expression might be critical for retinal Müller cells to clear the interstitial space from excess vasogenic edema and prevent maladaptive scarring in the retina during remote inflammatory processes of the CNS. KEY MESSAGES : Genetic ablation of AQP4 leads to a functional derangement of the retinal gliovascular unit with retinal hyperperfusion during autoimmune CNS inflammation. Genetic ablation of AQP4 results in a structural impairment of the blood retina barrier with extravasation of albumin during autoimmune CNS inflammation. Eventually, the lack of AQP4 in the retina during an inflammatory event prompts the exaggerated upregulation of GFAP as a hallmark of scarring as well as loss of retinal ganglion cells.
水通道蛋白 4（AQP4）是视神经脊髓炎（NMO）免疫反应的分子靶点，导致中枢神经系统（CNS）和视网膜的严重结构损伤。相反，AQP4 可能在多发性硬化症中作为星形胶质细胞的代偿性事件而上调。因此，AQP4 在神经炎症中的功能相关性需要确定。在这里，我们使用光学相干断层扫描（OCT）、OCT 血管造影、免疫组织化学、流式细胞术和基因表达分析，在野生型和 Aqp4 小鼠中测试了 AQP4 在 MOG(35-55)诱导的实验性自身免疫性脑脊髓炎（EAE）中的视网膜中的作用。在视网膜中未检测到炎症细胞的直接浸润。然而，TNF 和 Iba1 的早期视网膜表达表明，在 EAE 期间，视网膜以与野生型和 Aqp4 小鼠相似的方式参与炎症反应。虽然野生型小鼠迅速清除视网膜肿胀，但 Aqp4 动物表现出持续增加的视网膜厚度，伴有视网膜高灌注、白蛋白外渗以及 GFAP 的上调，这是 EAE 后期视网膜瘢痕形成的标志。最终，Aqp4 小鼠的视网膜神经节细胞丢失高于野生型小鼠。因此，AQP4 表达可能对视网膜 Müller 细胞清除间质空间中的血管源性水肿和防止 CNS 远程炎症过程中视网膜的适应性瘢痕形成至关重要。
AQP4 的基因缺失导致自身免疫性中枢神经系统炎症期间视网膜血管神经单元的功能障碍，伴有视网膜高灌注。AQP4 的基因缺失导致血视网膜屏障的结构损伤，伴有自身免疫性中枢神经系统炎症期间白蛋白的外渗。最终，在炎症事件中视网膜缺乏 AQP4 会促使 GFAP 的过度上调，作为瘢痕形成的标志以及视网膜神经节细胞的丢失。
