Role of SCARF1 in apoptotic cell clearance and prevention of autoimmunity

SCARF1 在凋亡细胞清除和预防自身免疫中的作用

基本信息

批准号：
9424643
负责人：
JOSEPH EL EL-KHOURY
金额：
$ 41.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9424643
关键词：
Amino Acids Apoptotic Autoantibodies Autoimmune Diseases Autoimmunity Binding Biochemical C57BL/6 Mouse CD36 gene Caenorhabditis elegans Cell membrane Cells Chromatin Chronic Clinical Complement Complement 1q Complex Confocal Microscopy Cytoplasmic Tail Data Defect Dendritic Cells Dermatitis Detection Development Disease Eating Endothelial Cells Excision Exposure to Extracellular Domain Failure Generations Genes Genetic Recombination Goals Homeostasis Homologous Protein Imaging Techniques Immune Cell Activation Immune system Immunology Immunoprecipitation In Vitro Inflammation Inflammatory Integral Membrane Protein Lead Lupus Maintenance Measures Mediating Molecular Mus Nature Nephritis Pathway interactions Patients Phagocytes Phagocytosis Pharmaceutical Preparations Phosphatidylserines Physiological Play Population Prevention Process Production Proteins Publications Regulation Research Resolution Role Signal Transduction Site-Directed Mutagenesis Symptoms System Systemic Lupus Erythematosus Testing Therapeutic Tissues Work cell injury cell type cytokine design in vivo intravital microscopy live cell imaging lupus-like macrophage new therapeutic target novel prevent public health relevance receptor scavenger receptor systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): Efficient detection and clearance of apoptotic cells is critical for control of tissue homeostasis. Professional phagocytes are responsible for removal of dying cells; however, defects in recognition or engulfment of apoptotic cells can lead to chronic inflammation and autoimmune disease. Accumulation of apoptotic cells in tissues has been associated with the autoimmune disease systemic lupus erythematosus (SLE), and several receptors on phagocytes responsible for apoptotic cell clearance have been identified. We recently discovered that the scavenger receptor SCARF1 plays an important role in sensing and engulfment of apoptotic cells. Dendritic cells use SCARF1 to capture apoptotic cells via C1q bound to exposed phosphatidylserine, a primary eat me signal that translocates from the inner to the outer leaflet of the cell membrane on dying cells. Scarf1 deficiency in mice leads to the accumulation of apoptotic cells in tissues and the spontaneous development of lupus-like autoimmune disease with the production of autoantibodies to chromatin, aberrant immune cell activation, dermatitis and nephritis. Our previous findings fill several major gaps in our understanding of apoptotic cell clearance and regulation of autoimmunity; however, additional work is needed to identify the mechanisms necessary for SCARF1-mediated removal of apoptotic cells and prevention of spontaneous autoimmunity in vivo. Because apoptotic cell clearance requires numerous receptors and bridging molecules in vivo, we hypothesize that the immune system has developed failsafe mechanisms involving multiple receptors and bridging proteins expressed by different cell types present in specific tissues for the removal of dying cells to maintain tolerance and prevent autoimmunity. To test these hypotheses we will, (1) determine the cell/tissue-specific role of Scarf1 deficiency in the spontaneous development of autoimmune disease; (2) determine the relative contribution of SCARF1, CD36 and C1q to apoptotic cell clearance and prevention of autoimmune disease; (3) define the domains in SCARF1 that mediate apoptotic cell recognition, phagocytosis, and signaling. Understanding the mechanisms by which discrete cell populations use SCARF1 to engulf apoptotic cells and prevent inflammation should enable the design of novel tailored drugs for autoimmune disorders by targeting SCARF1 in specific cell subsets.

描述（由申请人提供）：有效检测和清除凋亡细胞对于控制组织稳态至关重要。专业吞噬细胞负责清除死亡细胞；然而，凋亡细胞识别或吞噬的缺陷可能导致慢性炎症和自身免疫性疾病。组织中凋亡细胞的积累与自身免疫性疾病系统性红斑狼疮 (SLE) 有关，吞噬细胞上的几种受体负责我们最近发现清道夫受体 SCARF1 在凋亡细胞的感知和吞噬中发挥着重要作用，树突状细胞使用 SCARF1 通过与暴露的磷脂酰丝氨酸结合的 C1q 来捕获凋亡细胞，这是一种易位的主要“吃我”信号。小鼠死亡细胞中从细胞膜内层到外层的 Scarf1 缺陷会导致组织中凋亡细胞的积累。我们之前的发现填补了我们对凋亡细胞清除和自身免疫调节理解的几个主要空白；需要确定 SCARF1 介导的凋亡细胞清除和预防体内自发性自身免疫所需的机制，因为凋亡细胞清除需要大量的受体和细胞因子。在体内桥接分子中，我们努力认为免疫系统已经发展出故障安全机制，涉及特定组织中存在的不同细胞类型表达的多种受体和桥接蛋白，以去除垂死的细胞以维持耐受性并防止自身免疫。 (1) 确定 SCARF1 缺陷在自身免疫性疾病自发发展中的细胞/组织特异性作用；(2) 确定 SCARF1、CD36 和 C1q 对凋亡细胞清除和预防自身免疫性疾病的相对贡献(3) 定义 SCARF1 中介导凋亡细胞识别、吞噬作用和信号传导的结构域，了解离散细胞群使用 SCARF1 吞噬凋亡细胞并预防炎症的机制，应该能够设计出针对自身免疫性疾病的新型定制药物。靶向特定细胞亚群中的 SCARF1。