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：
9230810
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/9230810
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 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（适用提供）：凋亡细胞的有效检测和清除对于控制组织稳态至关重要。专业的吞噬细胞负责去除垂死的细胞。但是，识别或吞噬凋亡细胞的缺陷会导致慢性炎症和自身免疫性疾病。凋亡细胞在组织中的积累与自身免疫性疾病全身性红斑狼疮（SLE）有关，并且已经确定了负责凋亡细胞清除率的吞噬细胞上的几种受体。我们最近发现，清道夫受体疤痕1在凋亡细胞的敏感性和吞噬中起着重要作用。树突状细胞使用Scarf1通过C1Q捕获凋亡细胞，结合到暴露于磷脂酰丝氨酸的情况下，这是一种主要的饮食信号，从垂死细胞上的细胞膜内部转移到细胞膜的外部小叶。小鼠的SCARF1缺乏会导致组织中凋亡细胞的积累以及狼疮样的自身免疫性疾病的赞助者样发育，并产生自身抗体至染色质，异常免疫鼠激活，皮肤炎和肾炎。我们以前的发现填补了我们对凋亡细胞清除率和自身免疫调节的几个主要空白。但是，需要额外的工作来确定疤痕1介导的凋亡细胞去除所需的机制，并预防体内赞助商样的自身免疫性。由于凋亡细胞清除率需要体内众多受体和桥接分子，因此我们假设免疫系统已经开发了涉及多个受体和桥接蛋白质的故障安全机制，这些机制由存在于特定组织中的不同细胞类型表达的蛋白质表达，以消除垂死细胞的去除耐受性和预防自身免疫性。为了检验这些假设，我们将（1）确定Scarf1缺乏症在自身免疫性疾病的赞助发展中的细胞/组织特异性作用；（2）确定Scarf1，CD36和C1Q对凋亡细胞清除率的相对贡献以及自身免疫性疾病的预防；（3）定义Scarf1中的结构域，即中值凋亡细胞识别，吞噬作用和信号传导。了解离散细胞种群使用Scarf1吞噬凋亡细胞并防止炎症的机制，应通过针对特定细胞亚群中的Scarf1来设计新型的量身定制药物来用于自身免疫性疾病。