Da Cunha A P, Zhang Q, Prentiss M, Wu X Q, Kainz V, Xu Y Y, Vrouvlianis J, Li H, Rangaswamy N, Leehy B, McGee T L, Bell C L, Bigelow C E, Kansara V, Medley Q, Huang Q, Wu H Y
a Department of Ophthalmology , Novartis Institutes for Biomedical Research , Cambridge , Massachusetts , USA.
Curr Eye Res. 2018 Apr;43(4):553-565. doi: 10.1080/02713683.2017.1410180. Epub 2017 Dec 4.
The concept of tissue-dependent cytokine hierarchy has been demonstrated in a number of diseases, but it has not been investigated in ophthalmic diseases. Here, we evaluated the functional hierarchy of interleukin-1β (IL-1β), IL-6, IL-17A, and tumor necrosis factor (TNF) in the induction of ocular inflammation.
We delivered adeno-associated virus (AAV) vectors expressing IL-1β, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer. We also used an in vitro human system to test the effect of cytokines on barrier function.
We found that IL-1β had the highest ability to initiate ocular inflammation. The continuous overexpression of IL-1β resulted in a significant upregulation of additional proinflammatory mediators in the eye. Using scanning laser ophthalmoscope and optical coherence tomography imaging techniques, we showed that a low dose of AAVIL-1β was sufficient and was as pathogenic as a high dose of TNF in inducing vascular leakage, retinal degeneration, and cellular infiltration. Furthermore, only a marginal increase in IL-1β was enough to cause cellular infiltration, thus confirming the highly pathogenic nature of IL-1β in the eye. Contrary to our expectation, IL-6 or IL-17A had minimal or no effect in the eye. To examine the clinical relevance of our findings, we used an impedance assay to show that IL-1β alone or TNF alone was able to cause primary human retinal endothelial cell barrier dysfunction in vitro. Again, IL-6 alone or IL-17A alone had no effect on barrier function; however, in the presence of IL-1β or TNF, IL-17A but not IL-6 may provide additive proinflammatory effects.
Our studies demonstrate the existence of a functional hierarchy of proinflammatory cytokines in the eye, and we show that IL-1β is the most pathogenic when it is continuously expressed in the eye.
组织依赖性细胞因子层级概念已在多种疾病中得到证实，但尚未在眼科疾病中进行研究。在此，我们评估了白细胞介素-1β（IL-1β）、IL-6、IL-17A和肿瘤坏死因子（TNF）在诱导眼部炎症中的功能层级。
我们将表达IL-1β、IL-6、IL-17A或TNF的腺相关病毒（AAV）载体玻璃体内注射到未处理的C57/BL6小鼠中，并在AAV介导的基因转移5周后比较和对比眼部的炎症效应。我们还使用体外人源系统来测试细胞因子对屏障功能的影响。
我们发现IL-1β引发眼部炎症的能力最强。IL-1β的持续过表达导致眼部其他促炎介质显著上调。使用扫描激光检眼镜和光学相干断层扫描成像技术，我们表明低剂量的AAVIL-1β就足够了，并且在诱导血管渗漏、视网膜变性和细胞浸润方面与高剂量的TNF具有同等致病性。此外，仅IL-1β的少量增加就足以引起细胞浸润，从而证实了IL-1β在眼中的高致病性。与我们的预期相反，IL-6或IL-17A在眼中的作用极小或无作用。为了检验我们研究结果的临床相关性，我们使用阻抗测定法表明单独的IL-1β或单独的TNF能够在体外导致原代人视网膜内皮细胞屏障功能障碍。同样，单独的IL-6或单独的IL-17A对屏障功能无影响；然而，在存在IL-1β或TNF的情况下，IL-17A而非IL-6可能会提供额外的促炎作用。
我们的研究证明了眼中促炎细胞因子功能层级的存在，并且我们表明当IL-1β在眼中持续表达时，它是最具致病性的。
