Control of Dendritic Cell Function by the Lipopolysaccharide (LPS)-Responsive and Beige-like Anchor protein (Lrba)

脂多糖 (LPS) 响应性和米色样锚定蛋白 (Lrba) 对树突细胞功能的控制

基本信息

批准号：
10040959
负责人：
Emre Erol Turer
金额：
$ 12.26万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040959
关键词：
Address Affect Animals Autoimmunity Categories Cell physiology Cells Chronic Colitis Data Defect Dendritic Cells Dendritic cell activation Development Disease Endocytosis Endosomes Essential Genes Ethylnitrosourea Etiology Exhibits Extracellular Matrix Proteins FRAP1 gene Gastrointestinal Diseases Genes Genetic Diseases Genetic Screening Genetic study Goals Growth Factor Health Care Costs Homeostasis Human Human Genetics IRF3 gene Immune Immune signaling Induced Mutation Inflammation Inflammatory Bowel Diseases Innate Immune System Interferon Type I Interferons Intestinal Diseases Intestines Knock-out Knowledge Lead Lipopolysaccharides Maintenance Mass Spectrum Analysis Mendelian disorder Microbe Molecular Molecular Chaperones Mouse Protein Mus Mutation Nonsense Mutation PI3K/AKT Pathway interactions Peripheral Phagocytosis Phagolysosome Play Predisposition Production Protein Deficiency Proteins Proteome Receptor Signaling Role Signal Transduction Sodium Dextran Sulfate System TLR3 gene TLR7 gene Tissues Toll-like receptors United States Vesicle Wild Type Mouse Work cell type chemokine cytokine dextran sulfate sodium induced colitis enteritis experimental study genetic signature in vivo inflammatory disease of the intestine insight intestinal epithelium intestinal homeostasis macrophage pathogen prevent response stressor trafficking

项目摘要

Project Summary LRBA protein deficiency is a monogenic cause of autoimmunity and inflammatory bowel disease (IBD) in humans, but the basic cellular and molecular underpinnings responsible for the disease are not completely understood. In an ongoing forward genetic screen for N-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Lrba. We found that dendritic cells (DCs) contribute significantly to intestinal inflammation in Lrba- deficient mice. In response to the stimulation of the Toll-like receptors (TLRs) TLR3, TLR7, and TLR9, Lrba- /- DCs exhibited excessive chemokine and type I interferon production as well as exaggerated IRF3/7- and PI3K/mTORC1-dependent signaling. Knockout of Unc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes, caused a significant amelioration of the cytokine expression and colitis sensitivity after DSS treatment in Lrba-/- mice. Our data support a function for Lrba in restricting endosomal TLR signaling and subsequent intestinal inflammation. We propose to further elucidate the role of Lrba in innate immune cells in two interconnected and focused aims: Aim 1: To determine the role dendritic cell-intrinsic Lrba plays in experimental colitis. Aim 2: Elucidate the cellular trafficking defects of Lrba-/- dendritic cells that lead to exaggerated endosomal TLR responses. The aims in this proposal will help elucidate the mechanisms underlying the role of dendritic cells in tissue inflammation and the coordination of immune signaling within them.

项目概要 LRBA 蛋白缺乏是自身免疫和炎症性肠病 (IBD) 的单基因原因人类，但导致该疾病的基本细胞和分子基础并不完全明白了。在正在进行的 N-乙基-N-亚硝基脲 (ENU) 诱导突变的正向遗传筛选中，增加小鼠对右旋糖酐硫酸钠（DSS）诱导的结肠炎的易感性，我们发现了两个无稽之谈 Lrba 突变。我们发现树突状细胞 (DC) 对 Lrba- 肠道炎症有显着贡献缺乏的老鼠。为了响应 Toll 样受体 (TLR) TLR3、TLR7 和 TLR9 的刺激，Lrba- /- DC表现出过量的趋化因子和I型干扰素产生以及过度的IRF3/7-和 PI3K/mTORC1 依赖性信号传导。敲除 Unc93b1（TLR3 贩运所需的伴侣）， TLR7 和 TLR9 转入内涵体，可显着改善细胞因子表达和结肠炎 Lrba-/- 小鼠 DSS 治疗后的敏感性。我们的数据支持 Lrba 限制内体 TLR 的功能信号传导和随后的肠道炎症。我们建议进一步阐明 Lrba 在先天性中的作用免疫细胞有两个相互关联且集中的目标：目标 1：确定树突状细胞固有的 Lrba 的作用在实验性结肠炎中发挥作用。目标 2：阐明 Lrba-/- 树突状细胞的细胞运输缺陷，从而导致夸大的内体 TLR 反应。该提案的目标将有助于阐明潜在的机制树突状细胞在组织炎症中的作用及其内部免疫信号的协调。