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

细胞因子信号传导抑制剂 (SOCS) 对视网膜具有神经保护作用

• 批准号: 8339752
• 负责人: Charles E Egwuagu
• 金额: $ 16.39万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8339752
• 关键词: Animals; Apoptosis; Biopsy; Cell Proliferation; Cells; Cessation of life; Cytokine Inducible SH2-Containing Protein; Cytokine Signaling; Data; Defect; Disease; Embryonic Development; Ethics; Eye; Feedback; Guidelines; Immune response; Inflammation; Inflammatory; Insecta; Institutional Review Boards; Interferons; Mammals; Mediating; Modeling; Mus; PTPN6 gene; Pathologic; Pathway interactions; Patients; Peptides; Peripheral Blood Mononuclear Cell; Physarum polycephalum; Physiological; Physiological Processes; Production; Proteins; Rattus; Recruitment Activity; Regulation; Research; Retina; Retinal; Role; Scleritis; Signal Transduction; T-Lymphocyte; Tissues; Transgenic Mice; United States National Institutes of Health; Up-Regulation; Uveitis; chemokine; cytokine; genetic regulatory protein; in vivo; mimetics; protein inhibitors of activated STAT; transcription factor

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.

本研究的目的之一是调查持续性眼部炎症性疾病患者细胞因子分泌的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 指南不允许进行视网膜组织活检来确定巩膜炎患者眼组织中 SOCS 表达是否也有缺陷，因此我们培育了视网膜中 SOCS1 过度表达的转基因小鼠和大鼠，并利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。尽管多项研究结果表明，炎症细胞诱导 SOCS1、SOCS3 和 CIS 可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，但迄今为止，尚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发挥的生理作用。通过将 SOCS1 的过度表达靶向大鼠和小鼠的视网膜，并在充分表征的 EAU 模型中检查 SOCS1 的体内功能，我们发现 SOCS1 可以保护小鼠和大鼠免于发生严重的葡萄膜炎。我们的数据表明，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，这导致葡萄膜炎期间招募到视网膜的致病性 T 细胞数量大幅减少。巩膜炎患者中 SOCS1 的表达缺陷，加上我们的数据表明 SOCS1 介导保护神经视网膜细胞免于凋亡，表明 SOCS1 在视网膜中具有神经保护功能，并意味着 SOCS1 模拟肽的施用可能有助于治疗葡萄膜炎或巩膜炎。