Suppressors of Cytokine Signalling (SOCS) have Neuroprotective Roles in Retina

我们在这项研究中的目的之一是调查持续性眼炎性疾病患者细胞因子分泌异常上调是否部分源于介导促炎细胞因子活性负反馈调节的蛋白质缺陷。我们发现巩膜炎患者的PBMC不能诱导负反馈调节蛋白SOCS1的表达。由于伦理考虑和NIH IRB指南排除了获得视网膜组织活检以确定硬化症患者眼组织中SOCS表达是否也存在缺陷的可能性，我们培育了在视网膜中过度表达SOCS1的转基因小鼠和大鼠，并使用这些动物进一步研究SOCS1在视网膜和眼内炎症性疾病中的作用。尽管一些研究结果表明，炎症细胞诱导SOCS1、SOCS3和CIS通过调节细胞因子信号的强度和持续时间来减轻免疫反应，但到目前为止，人们还不清楚视网膜细胞是否也产生SOCS1，以及它们在眼部炎症过程中可能起到什么生理作用。通过靶向SOCS1在大鼠和小鼠视网膜的过度表达，并在EAU模型中检测SOCS1的体内功能，我们发现SOCS1可以保护小鼠和大鼠免受严重葡萄膜炎的影响。我们的数据表明，在EAU期间产生的促炎细胞因子诱导视网膜细胞抑制趋化细胞因子的产生，这导致在葡萄膜炎期间招募到视网膜的致病T细胞的数量显著减少。SOCS1在巩膜炎患者中的表达缺陷，结合我们的研究结果表明，SOCS1介导了对神经视网膜细胞的保护作用，提示SOCS1在视网膜具有神经保护作用，并暗示SOCS1模拟肽的应用可能有助于葡萄膜炎或巩膜炎的治疗。

One of our objectives in this study was to investigate whether the aberrant upregulation of cytokine secretion in patients with persistent ocular inflammatory disease derives in part from defects in proteins that mediate negative feedback regulation of activities of proinflammatory cytokine. We found that PBMC of patients with scleritis could not induce the expression of the negative feedback regulatory protein SOCS1. Because ethical considerations and NIH IRB guidelines precluded obtaining retinal tissue biopsy to determine whether SOCS expression is also defective in ocular tissues of scleritis patients, we generated transgenic mice and rats with over-expression of SOCS1 in the retina and used these animals to further investigate the role of SOCS1 in the retina and intraocular inflammatory diseases. Although results from several studies suggest that induction of SOCS1, SOCS3 and CIS by inflammatory cells mitigates immune responses by regulating the intensity and duration of cytokine signals, until now it has not been clear whether retinal cells also produce SOCS1 and what physiological role they might have during ocular inflammation. By targeting the over-expression of SOCS1 to the retina of rats and mice and examining the in vivo function of SOCS1 in the well-characterized EAU model, we show that SOCS1 protects mice and rats from developing severe uveitis. Our data suggests that proinflammatory cytokines produced during EAU induces retinal cells to repress the production of chemotactic cytokines and this results in substantial decrease in the numbers of pathogenic T cells recruited into the retina during uveitis. Defective expression of SOCS1 in patients with scleritis, taken together with our data showing that SOCS1 mediated protection of neuroretinal cells from apoptosis, suggests that SOCS1 has neuroprotective function in the retina and imply that administration of SOCS1 mimetic peptides maybe useful in treating uveitis or scleritis.