Immune Privilege, Müller cells, and Autophagy

免疫特权、Müller 细胞和自噬

• 批准号: 10501886
• 负责人: Thomas Almon Ferguson
• 金额: $ 43.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501886
• 关键词: Anti-Inflammatory Agents; Autoimmune Diseases; Autophagocytosis; Bacteria; Biological Process; Blindness; Blood-Retinal Barrier; Cell physiology; Cells; Cellular biology; Data; Degradation Pathway; Development; Disease; Disease model; Eating; Elements; Endotoxins; Eye; Eye diseases; Failure; Genes; Homeostasis; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Keratoplasty; Lead; Ligands; Mediating; Minor; Mitochondria; Modeling; Molecular; Morphology; Muller' s cell; Mus; Nature; Neuroglia; Neurotransmitters; Organ; Participant; Pathogenicity; Pathway interactions; Phagocytes; Phagocytosis; Photoreceptors; Process; Production; Property; Receptor Cell; Recycling; Resistance; Retina; Retinal Degeneration; Retinal Diseases; Role; Site; Stress; System; T cell response; T-Cell Receptor; Testing; Thick; Tissues; Toll-like receptors; Uveitis; Virus Diseases; Vision; Vitamin A; antigen-specific T cells; arm; autoimmune uveitis; base; cell injury; cytokine; extracellular; immunoregulation; neuroprotection; novel; novel strategies; prevent; protein aggregation; response; retinal damage; single-cell RNA sequencing; virtual; visual cycle

Abstract Immune privilege is a term applied to organs such as the eye that have a unique relationship with the immune response. These sites prohibit the spread of inflammation since even minor episodes can threaten vision. The breakdown of immune privilege is thought to have serious consequences for the eye; however, in spite its powerful influence on inflammation we know little about how immune privilege influences retinal diseases. Müller cells are the major glial cell of the retina that maintain structural integrity. They react in virtually every eye disease but are strikingly resistant damage; importantly they can suppress inflammation. Based on this they should be key participants in immune privilege, but this is not understood. The biological process of autophagy (literally self-eating) is a recycling system that destroys inflammation-inducing cellular debris to prevent tissue damage. Because immune privilege, Müller cells, and autophagy all have anti- inflammatory properties, we will test the novel hypothesis that Müller glial cells utilize the autophagy pathway to support the anti-inflammatory nature of the eye (i.e. immune privilege). We will do this by examining intraocular inflammation in 2 well-characterized disease models, endotoxin induced uveitis (EIU) and experimental autoimmune uveitis (EAU), utilizing mice with autophagy-deficient retinal Müller cells. Since EIU is mediated by the innate arm of the immune system and EAU is an antigen specific T cell mediated disease we will get thorough understanding as to how Müller cell autophagy influences different types of immune mediated diseases of the eye. In Aim 1 we will assess the intraocular inflammatory response in these models by comparing control mice with mice that have had the essential autophagy genes Atg5 and Fip200 deleted specifically in Müller glial cells. We will evaluate inflammatory infiltrates, cytokine production, and retinal integrity in both models. Preliminary data suggests that inflammation and retinal damage are enhanced in the presence of autophagy deficient Müller cells in both models. In Aim 2 we will we will define the molecular basis of these enhanced inflammatory response to determine the contribution of autophagy to immunoregulatory properties of Müller cells in the eye. Studies will include scRNA-seq analysis, examination of the blood retinal barrier, analysis of the T-cell response in EAU, and morphological analysis. In Aim 3 we will test the idea that autophagy supports phagocytosis in Müller cells promoting their anti-inflammatory properties using the process of LC3-associated phagocytosis (or LAP). We will test whether LAP recovers a portion of the vitamin A for the Müller visual cycle. By elucidating the role of Müller cells and autophagy in immune privilege we will better understand their influence on ocular inflammatory responses. Thus, rather than just treating inflammation, we could consider upregulating immune privilege alone, or in combination with other treatments, to target retinal disease.

摘要 免疫特免权是一个术语，适用于眼睛等与 免疫反应。这些网站阻止炎症的传播，因为即使是轻微的发作也可能威胁到 幻象。免疫特权的崩溃被认为对眼睛有严重的后果；然而，在 尽管免疫豁免对炎症有强大的影响，但我们对免疫豁免如何影响视网膜知之甚少 疾病。米勒细胞是视网膜中维持结构完整性的主要神经胶质细胞。他们的反应是 几乎所有的眼科疾病，但都是惊人的抵抗损害；重要的是，他们可以抑制炎症。 基于这一点，他们应该是免疫特权的关键参与者，但这一点还不被理解。生物学的 自噬过程(字面意思是自噬)是一种循环系统，它摧毁了引发炎症的细胞 碎片以防止组织损伤。因为免疫豁免、Müler细胞和自噬都有抗 炎症特性，我们将检验Müler神经胶质细胞利用自噬途径 支持眼睛的抗炎特性(即免疫特权)。我们将通过检查 两种典型疾病模型的眼内炎症：内毒素诱导性葡萄膜炎和 实验性自身免疫性葡萄膜炎(EAU)，利用自噬缺陷的视网膜Müler细胞的小鼠。自EIU以来 是由免疫系统的先天手臂介导的，而EAU是一种抗原特异性T细胞介导的疾病 我们将彻底了解Müler细胞自噬如何影响不同类型的免疫 传播的眼部疾病。在目标1中，我们将评估这些模型的眼内炎症反应。 通过比较对照小鼠和缺失了必要的自噬基因ATG5和FIP200的小鼠 尤其是在Müler胶质细胞中。我们将评估炎症浸润物、细胞因子产生和视网膜 在两种模式中都是完整的。初步数据显示，炎症和视网膜损伤在 在两种模型中都存在自噬缺陷的Müler细胞。在目标2中，我们将定义分子基础 这些增强的炎症反应以确定自噬对免疫调节的贡献 眼内Müler细胞的特性。研究将包括scrna-seq分析，血视网膜检查。 屏障，分析EAU中的T细胞反应，以及形态分析。在目标3中，我们将测试这样的想法 自噬支持Müler细胞的吞噬作用，通过该过程促进其抗炎特性 与LC3相关的吞噬作用(或LAP)。我们将测试LAP是否能回收一部分维生素A 米勒视觉循环。通过阐明Müler细胞和自噬在免疫豁免中的作用，我们将更好地 了解它们对眼部炎症反应的影响。因此，我们不仅治疗炎症，还 可以考虑单独上调免疫特免权，或与其他治疗方法联合使用，以针对视网膜 疾病。