Functional significance of NETosis to intraocular inflammation

NETosis 对眼内炎症的功能意义

• 批准号: 9906934
• 负责人: Kathryn Pepple
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906934
• 关键词: Animal Model; Anterior uveitis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Blindness; Cell Death; Chemicals; Chromatin Fiber; Clinical; Complement; DNA Sequence Alteration; Data; Development; Disease; Effector Cell; Enzyme-Linked Immunosorbent Assay; Experimental Models; Eye; Flow Cytometry; Genetic; Goals; Histology; Human; Immune response; Immunohistochemistry; In Vitro; Infection; Inflammation; Inflammatory; Intermediate Uveitis; Knowledge; Lead; Leucocytic infiltrate; Leukocyte L1 Antigen Complex; Liquid substance; Literature; Measures; Modeling; Monitor; Mus; Natural Immunity; Neutrophil Infiltration; Organ; Patients; Play; Process; Proteins; Role; S100A8 gene; S100A9 gene; Severities; Sterility; Structure; T-Lymphocyte; Testing; Time; United States; Uveitis; Visual impairment; adaptive immunity; antimicrobial; aqueous; autoimmune uveitis; drug development; extracellular; fighting; human disease; improved; insight; microbial; mycobacterial; neutrophil; new therapeutic target; novel; novel therapeutics; pre-clinical; therapeutic target

Abstract Uveitis can result in severe visual impairment, and ranks fifth among causes of blindness in the United States. Yet we are still trying to develop a complete understanding of the mechanisms of non- infectious intraocular inflammation. Expanding our knowledge of the role innate immunity plays in non- infectious inflammatory disease will provide important insights to complement the large body of literature on the role adaptive immunity, particularly T-cells, play in intraocular inflammation. Neutrophils are important innate immunity effector cells, and have been identified in human eyes with uveitis as well as in experimental models of uveitis. Neutrophils can undergo a form of cell death known as NETosis as part of the host response to infection, or during sterile inflammation in autoimmune diseases. The resulting neutrophil extracellular traps (NETs) can be pro-inflammatory, and blocking NETosis has been shown to ameliorate inflammation in animal models of systemic inflammatory diseases. Despite the presence of neutrophils in inflamed eyes, the presence of NETs in uveitis has not been explored. We have preliminary data identifying NETs in an animal model of anterior and intermediate uveitis, primed mycobacterial uveitis (PMU). We propose using both PMU and experimental autoimmune uveitis (EAU) to determine if NETs are generally present in the case of intraocular inflammation (Aim 1). We will also determine the functional importance of NETs to uveitis by testing the sufficiency of NETs to generate uveitis and the impact of blocking NETosis with genetic and chemical inhibition (Aim 2). These studies will advance the field of innate immunity in ocular inflammation, and provide pre-clinical evidence for NETosis as a therapeutic target for drug development of new treatments for patients with uveitis.

摘要 葡萄膜炎可导致严重的视力损害，在世界上致盲原因中排名第五。 美国的然而，我们仍在努力发展一个完整的理解的机制，非- 感染性眼内炎症扩大我们对先天免疫在非免疫性疾病中所起作用的认识， 传染性炎症疾病将提供重要的见解，以补充庞大的机构， 关于获得性免疫，特别是T细胞在眼内炎症中的作用的文献。中性粒 是重要的先天免疫效应细胞，并且在患有葡萄膜炎的人眼中也被鉴定出 就像葡萄膜炎的实验模型一样。中性粒细胞可以经历一种称为NETosis的细胞死亡形式 作为宿主对感染的反应的一部分，或在自身免疫性疾病的无菌炎症期间。的 由此产生的中性粒细胞胞外陷阱（NETs）可以是促炎性的， 在全身性炎症性疾病的动物模型中显示改善炎症。尽管 尽管在发炎的眼睛中存在嗜中性粒细胞，但还没有探索在葡萄膜炎中存在NET。 我们有初步的数据，确定在动物模型的前和中间NET 葡萄膜炎，致敏分枝杆菌葡萄膜炎（PMU）。我们建议使用PMU和实验 自身免疫性葡萄膜炎（EAU），以确定NETs是否普遍存在于眼内 炎症（目的1）。我们还将通过测试 NETs足以产生葡萄膜炎以及用遗传和化学物质阻断NETosis的影响 抑制（目的2）。这些研究将推进眼部炎症中的先天免疫领域， 为NETosis作为新药开发的治疗靶点提供临床前证据 葡萄膜炎患者的治疗。