Functional significance of NETosis to intraocular inflammation

摘要 葡萄膜炎会导致严重的视力障碍，在全球致盲原因中排名第五。 美国。然而，我们仍在努力发展对非致病机制的完整理解 感染性眼内炎。扩大我们对先天免疫在非传染性疾病中的作用的了解 传染性炎症性疾病将提供重要的见解，以补充庞大的身体 有关获得性免疫，特别是T细胞在眼内炎症中所起作用的文献。中性粒细胞 是重要的先天免疫效应细胞，在患葡萄膜炎的人眼中也被发现。 就像葡萄膜炎的实验模型一样。中性粒细胞会经历一种称为网织红细胞增多症的细胞死亡 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。这个 由此产生的中性粒细胞胞外陷阱(NETs)可能是促炎的，并已阻断NETsis 在全身性炎症性疾病的动物模型中显示出改善炎症的作用。尽管 中性粒细胞在发炎的眼睛中的存在，网状病毒在葡萄膜炎中的存在还没有被探索。 我们有初步的数据在前部和中间部的动物模型中识别Net 葡萄膜炎，细菌性葡萄膜炎(PMU)。我们建议同时使用PMU和实验 自身免疫性葡萄膜炎(EAU)以确定眼内是否普遍存在Net 炎症(目标1)。我们还将通过测试Net对葡萄膜炎的功能重要性来确定 Net是否足以引起葡萄膜炎以及用遗传和化学方法阻断Net病的影响 抑制(目标2)。这些研究将推进眼部炎症的先天免疫领域，并 为NETsis作为新药开发靶点提供临床前证据 葡萄膜炎患者的治疗。

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.