Immune Privilege, Müller cells, and Autophagy

免疫特权、Müller 细胞和自噬

基本信息

批准号：
10680566
负责人：
Thomas Almon Ferguson
金额：
$ 41.11万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10680566
关键词：
Ablation Anti-Inflammatory Agents Autoimmune Diseases Autoimmunity 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 Ligands Macrophage Mediating Minor Mitochondria Modeling Molecular Morphology Muller&apos s cell Mus Nature Neuroglia Neurotransmitters Organ Participant Pathogenicity Pathway interactions Phagocytes Phagocytosis Photoreceptors Process Production Property Reaction 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 cell injury cytokine extracellular immunoregulation neuroprotection novel novel strategies prevent protein aggregation response retinal damage single-cell RNA sequencing virtual visual cycle

项目摘要

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.

抽象的免疫特权是一个术语，适用于与眼睛等具有独特关系的器官。这些部位会阻止炎症的传播，因为即使是轻微的发作也会造成威胁。然而，免疫特权的破坏被认为会对眼睛产生严重后果。尽管它对炎症有强大的影响，但我们对免疫特权如何影响视网膜知之甚少穆勒细胞是视网膜中维持结构完整性的主要神经胶质细胞。几乎所有眼部疾病都具有显着的抵抗力；重要的是它们可以抑制炎症。基于此，他们应该是免疫特权的关键参与者，但这在生物学上尚不为人所知。自噬（字面意思是自食）过程是一种破坏诱导炎症细胞的回收系统因为免疫特权、Müller 细胞和自噬都具有抗- 炎症特性，我们将测试 Müller 胶质细胞利用自噬途径的新假设支持眼睛的抗炎性质（即免疫特权）我们将通过检查来做到这一点。两种特征明确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。由免疫系统先天臂介导，EAU 是一种抗原特异性 T 细胞介导的疾病我们将深入了解穆勒细胞自噬如何影响不同类型的免疫在目标 1 中，我们将评估这些模型中的眼内炎症反应。通过将对照小鼠与删除必需自噬基因 Atg5 和 Fip200 的小鼠进行比较特别是在穆勒神经胶质细胞中，我们将评估炎症浸润、细胞因子的产生和视网膜。两种模型的完整性表明，炎症和视网膜损伤均增强。在两个模型中都存在自噬缺陷的 Müller 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研究将包括 scRNA-seq 分析、血视网膜检查。屏障、EAU 中 T 细胞反应的分析以及形态学分析在目标 3 中，我们将测试以下想法：自噬支持 Müller 细胞的吞噬作用，利用该过程促进其抗炎特性我们将测试 LAP 是否回收了部分维生素 A。通过阐明穆勒细胞和自噬在免疫特权中的作用，我们将更好地了解穆勒视觉循环。它们对眼部炎症反应的影响因此，我们不仅仅是治疗炎症。可以考虑单独上调免疫特权，或与其他治疗相结合，以针对视网膜疾病。