Regulation of JAK/STAT pathways in the eye

眼睛中 JAK/STAT 通路的调节

• 批准号: 7734606
• 负责人: Charles E Egwuagu
• 金额: $ 33.65万
• 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/7734606
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Attention; Autoimmune Process; CD4 Positive T Lymphocytes; Cells; Central Nervous System Diseases; Development; Disease; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Eye; Homeostasis; Human; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-12; Interleukin-17; Knockout Mice; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Outcome; Pathogenesis; Pathway interactions; Process; Regulation; Reporting; Resistance; Retina; Role; STAT3 gene; Sarcoidosis; Scleritis; Sympathetic Ophthalmia; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Tissues; Uncertainty; Uveitis; Vision; cell type; prevent; research study; retinochoroidopathy; therapeutic target; uveoretinitis

Uveitis is a group of sight-threatening intraocular inflammatory diseases that includes Behet's disease, birdshot retinochoroidopathy, Vogt-Koyanagi-Harada's, sympathetic ophthalmia, ocular sarcoidosis. Studies of experimental autoimmune uveoretinitis (EAU), the model of uveitis led to the conclusion that Th1 cells are the etiologic agent of uveitis because IFN-gamma levels are elevated in the retina during uveitis and IL12p40 is required for EAU induction. However, subsequent studies revealed that IL-12 down-regulates EAU and treatment of mice with EAU with anti-IFN-gamma antibodies was found to exacerbate the disease, casting doubts on the role of this T cell subset as the etiologic agent of uveitis. Recent reports implicating Th17 cells in pathogenesis of human uveitis and scleritis has further complicated our understanding of the role of different T cell subsets in uveitis. Besides Th1 and Th17 cells, Th2 and Treg are also detected in the eye during uveitis and exact roles of these T cell subtypes in the immunopathogenic process are largely unknown. Thus in context of treating uveitis, it is important to note that presence of T cells in the retina compromises vision and preventing entry of all T cell types or limiting their expansion in the eye is of utmost importance. Accordingly, identifying molecular pathways amendable to therapeutic targeting has attracted attention as a potential strategy for limiting expansion of uveitogenic T cells in the eye. Recent reports indicating requirement of STAT3 for commitment of naive T cells towards the Th17 developmental pathway, suggest a potential involvement of STAT3 pathway in mediating CNS inflammatory diseases. In this study, we have generated mice with targeted deletion of STAT3 in the CD4+ T cell compartment (CD4Stat3-/-) and used them to examine whether STAT3 pathways are required for development of EAU, as well as, experimental autoimmune encephalomyelitis (EAE), another CNS disease that shares essential immunopathologic features as EAU. Here, we have shown that unlike the partial protection conferred by IL-17 blockage with IL-17 Abs, CD4stat3-/- mice are completely resistant to EAU or EAE and this dramatic outcome derives from combinatory mechanisms that include: IL-17 blockade; altered T cell homeostasis that favor expansion of anti-inflammatory responses; inhibition of T cell entry to CNS tissues. Resistance of STAT3 conditional knockout mice to development of EAE and EAU suggest that the STAT3 pathway is a potential therapeutic target for modulating these CNS inflammatory diseases.

葡萄膜炎是一组视力危及的眼内炎症性疾病，包括Behet疾病，视网膜视网膜疾病，Vogt-Koyanagi-Harada，交感神经性眼科，眼角病。实验性自身免疫性葡萄膜炎（EAU）的研究，葡萄膜炎的模型得出的结论是，Th1细胞是葡萄膜炎的病因学药物，因为在葡萄膜炎和IL12P40期间，IFN-gamma水平升高了EAU诱导所需的IL12P40。然而，随后的研究表明，IL-12下调EAU并用抗IFN-gamma抗体对EAU进行治疗会加剧这种疾病，对这种T细胞子群作为葡萄膜炎的病因学的作用产生了怀疑。最近的报道暗示了Th17细胞在人葡萄膜炎和硬化炎的发病机理中，使我们对不同T细胞子群在葡萄膜炎中的作用的理解变得复杂。除Th1和Th17细胞外，在葡萄膜炎期间，在眼睛中还检测到Th2和Treg在免疫发病过程中这些T细胞亚型的确切作用在很大程度上是未知的。因此，在治疗葡萄膜炎的情况下，重要的是要注意，视网膜中T细胞的存在会损害视力并防止所有T细胞类型的进入或限制其在眼中的膨胀至关重要。 因此，识别可以对治疗靶向进行修正的分子途径已引起人们的关注，这是限制眼睛中葡萄膜的T细胞扩展的潜在策略。最近的报告表明，STAT3对NAIVE T细胞对TH17发育途径的承诺的要求表明，STAT3途径可能参与介导CNS炎症性疾病。在这项研究中，我们在CD4+ T细胞室（CD4STAT3 - / - ）中产生了针对STAT3的靶向缺失的小鼠，并使用它们来检查STAT3途径是否需要开发EAU以及实验性的自身免疫性脑脊髓炎（EAE），另一种CNS疾病，另一种CNS疾病，具有基本的免疫疾病。在这里，我们已经表明，与IL-17阻塞与IL-17 ABS所赋予的部分保护不同，CD4STAT3 - / - 小鼠完全抵抗EAU或EAE，而这种戏剧性的结果来自包括：IL-17封锁的组合机制；改变了T细胞稳态，有利于扩展抗炎反应的扩展；抑制T细胞进入中枢神经系统组织。 STAT3条件敲除小鼠对EAE和EAU的发展的抗性表明，STAT3途径是调节这些中枢神经系统炎症性疾病的潜在治疗靶点。