CIISA - Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade Técnica, 1300-477, Lisbon, Portugal; CBATEG - Center for Animal Biotechnology and Gene Therapy, Autonomous University of Barcelona, C/ de La Vall Morona, 08193, Bellaterra (Cerdanyola Del Vallès), Spain.
CBATEG - Center for Animal Biotechnology and Gene Therapy, Autonomous University of Barcelona, C/ de La Vall Morona, 08193, Bellaterra (Cerdanyola Del Vallès), Spain; Department of Animal Health and Anatomy, Faculty of Veterinary, Autonomous University of Barcelona, Travessera Del Turons, 08193, Bellaterra (Cerdanyola Del Vallès), Spain.
Exp Eye Res. 2021 Jan;202:108292. doi: 10.1016/j.exer.2020.108292. Epub 2020 Oct 13.
Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.
视网膜中铁的有效控制对于维持铁稳态至关重要，因为铁的失衡与氧化应激和多种视网膜病变的进展有关。铁蛋白因其在铁储存和解毒中的作用而被认为是一种铁转运蛋白，通过与 Scara5 和 TIM2 膜受体结合。在这项研究中，研究了 TIM2 在小鼠视网膜中的存在及其与铁相关的功能。我们的研究结果首次揭示了 TIM2 受体在小鼠视网膜中的存在，主要存在于 Muller 细胞中。实验下调 TIM2 在小鼠视网膜中的表达，可能由于代偿机制，Scara5 过表达增加了视网膜铁蛋白的摄取，并导致铁过载。随后的活性氧（ROS）过度产生和血管内皮生长因子（VEGF）过度表达导致细胞旁和细胞间内皮转运受损，表现为紧密连接降解和 caveolae 数量增加。结果，观察到血视网膜屏障（BRB）破坏和视网膜水肿。总之，这些结果表明 TIM2 是视网膜铁稳态的新调节剂，也是对抗视网膜病变的潜在靶点。
