Department of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, Electron Microscope Laboratory, Tulane University, New Orleans, Louisiana 70118, Department of Ophthalmology, Georgia Health Sciences University, Augusta, Georgia 30912, and Jules Stein Eye Institute, The University of California, Los Angeles School of Medicine, Los Angeles, California 90095.
J Neurosci. 2013 Oct 30;33(44):17458-68. doi: 10.1523/JNEUROSCI.1380-13.2013.
Interphotoreceptor retinoid-binding protein (IRBP) secreted by photoreceptors plays a pivotal role in photoreceptor survival with an unknown mechanism. A mutation in the human IRBP has been linked to retinitis pigmentosa, a progressive retinal degenerative disease. Mice lacking IRBP display severe early and progressive photoreceptor degeneration. However, the signaling pathway(s) leading to photoreceptor death in IRBP-deficient mice remains poorly understood. Here, we show that amounts of tumor necrosis factor-α (TNF-α) in the interphotoreceptor matrix and retinas of Irbp(-/-) mice were increased more than 10-fold and fivefold, respectively, compared with those in wild-type mice. Moreover, TNF-α receptor 1, an important membrane death receptor that mediates both programmed apoptosis and necrosis, was also significantly increased in Irbp(-/-) retina, and was colocalized with peanut agglutinin to the Irbp(-/-) cone outer segments. Although these death signaling proteins were increased, the caspase-dependent and independent apoptotic pathways were mildly activated in the Irbp(-/-) retinas, suggesting that other cell death mechanism(s) also contributes to the extensive photoreceptor degeneration in Irbp(-/-) retina. We found that receptor interacting protein 1 and 3 (RIP1 and RIP3) kinases, the intracellular key mediators of TNF-induced cellular necrosis, were elevated at least threefold in the Irbp(-/-) retinas. Moreover, pharmacological inhibition of RIP1 kinase significantly prevented cone and rod photoreceptor degeneration in Irbp(-/-) mice. These results reveal that RIP kinase-mediated necrosis strongly contributes to cone and rod degeneration in Irbp(-/-) mice, implicating the TNF-RIP pathway as a potential therapeutic target to prevent or delay photoreceptor degeneration in patients with retinitis pigmentosa caused by IRBP mutation.
光感受器分泌的间视网膜视黄醇结合蛋白（IRBP）在光感受器存活中起着关键作用，但其机制尚不清楚。人类 IRBP 的突变与一种进行性视网膜退行性疾病——色素性视网膜炎有关。缺乏 IRBP 的小鼠表现出严重的早期和进行性光感受器变性。然而，IRBP 缺陷型小鼠中导致光感受器死亡的信号通路仍知之甚少。在这里，我们发现与野生型小鼠相比，IRBP(-/-) 小鼠的光感受器间基质和视网膜中的肿瘤坏死因子-α（TNF-α）含量分别增加了 10 多倍和 5 倍。此外，TNF-α受体 1，一种重要的膜死亡受体，介导程序性细胞凋亡和坏死，在 Irbp(-/-) 视网膜中也显著增加，并且与花生凝集素一起定位于 Irbp(-/-) 锥体外节。尽管这些死亡信号蛋白增加，但 caspase 依赖性和非依赖性凋亡途径在 Irbp(-/-) 视网膜中仅轻度激活，这表明其他细胞死亡机制也有助于 Irbp(-/-) 视网膜中广泛的光感受器变性。我们发现，受体相互作用蛋白 1 和 3（RIP1 和 RIP3）激酶是 TNF 诱导的细胞坏死的细胞内关键介质，在 Irbp(-/-) 视网膜中至少升高了三倍。此外，RIP1 激酶的药理学抑制显著阻止了 Irbp(-/-) 小鼠中锥体和杆状光感受器的变性。这些结果表明，RIP 激酶介导的坏死强烈导致 Irbp(-/-) 小鼠中的锥体和杆状光感受器变性，提示 TNF-RIP 途径可能成为预防或延迟由 IRBP 突变引起的色素性视网膜炎患者光感受器变性的潜在治疗靶点。
