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 免疫豁免是一个术语，适用于与免疫系统有独特关系的器官，如眼睛。 免疫反应这些部位阻止了炎症的扩散，因为即使是轻微的发作也会威胁到 视野免疫特权的崩溃被认为对眼睛有严重的后果;然而， 尽管它对炎症有强大的影响，但我们对免疫豁免如何影响视网膜病变知之甚少。 疾病Müller细胞是维持结构完整性的视网膜的主要神经胶质细胞。他们的反应是 几乎所有的眼睛疾病，但惊人的抵抗损害;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，但这一点并不清楚。生物 自噬过程（字面意思是自噬）是一个破坏炎症诱导细胞的循环系统， 碎片，以防止组织损伤。因为免疫赦免、米勒细胞和自噬都有抗- 我们将测试新的假设，即Müller神经胶质细胞利用自噬途径， 支持眼睛的抗炎性质（即免疫豁免）。我们将通过检查 在2种充分表征的疾病模型中的眼内炎症，内毒素诱导的葡萄膜炎（EIU）和 实验性自身免疫性葡萄膜炎（EAU），利用具有自噬缺陷的视网膜Müller细胞的小鼠。自从EIU EAU是由免疫系统的先天臂介导的，EAU是抗原特异性T细胞介导的疾病 我们将深入了解Müller细胞自噬如何影响不同类型的免疫系统， 介导的眼部疾病。在目标1中，我们将评估这些模型中的眼内炎症反应 通过将对照小鼠与缺失了必需的自噬基因Atg 5和Fip 200的小鼠进行比较， 尤其是在米勒神经胶质细胞中。我们将评估炎性浸润，细胞因子的产生，以及视网膜病变。 在两种模式中的完整性。初步的数据表明，炎症和视网膜损伤是加强在 两种模型中都存在自噬缺陷的穆勒细胞。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， Müller细胞在眼睛中的作用研究将包括scRNA-seq分析，血液视网膜检查， 屏障、EAU中T细胞应答的分析和形态学分析。在目标3中，我们将测试以下想法： 自噬支持Müller细胞中的吞噬作用，利用该过程促进其抗炎特性 LC 3相关的吞噬作用（或吞噬）。我们将测试维生素A是否能在体内恢复一部分维生素A， 缪勒视觉循环通过阐明Müller细胞和自噬在免疫赦免中的作用，我们将更好地 了解它们对眼部炎症反应的影响。因此，我们不仅要治疗炎症， 我可以考虑单独上调免疫赦免，或与其他治疗方法联合，以靶向视网膜病变。 疾病