TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown

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 Willer 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.

Automated summary

The study revealed the presence of TIM2 receptors in the mouse retina and showed that experimental TIM2 downregulation increased Scara5 expression, promoting retinal ferritin uptake and inducing iron overload. This led to ROS overproduction and VEGF overexpression, resulting in impaired endothelial transport, BRB breakdown, and retinal edema. These findings suggest that TIM2 could be a potential target to counteract retinopathy by modulating retinal iron homeostasis.