Role of SCARF1 in removal of apoptotic debris and protection against autoimmunity

SCARF1 在清除细胞凋亡碎片和防御自身免疫方面的作用

基本信息

批准号：
10409829
负责人：
Zaida Gisela Ramirez-Ortiz
金额：
$ 20.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-24 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409829
关键词：
Address Affinity Amino Acids Apoptotic Autoantibodies Autoimmune Diseases Autoimmunity Binding Biochemical Biological Assay Blood Bone Marrow C-terminal Cell Maturation Cells Chimera organism Chromatin Chronic Clinical Communicable Diseases Complement Complement 1q Complex Cysteine Cytoplasmic Tail Defect Dendritic Cells Dermatitis Detection Development Disease Elements Endothelial Cells Epidermal Growth Factor Event Excision Extracellular Domain Failure Generations Goals Hematopoietic Homeostasis Imaging Techniques Immune Tolerance Immune response Immune system Immunology Impairment In Vitro Inflammation Integral Membrane Protein Lead Ligand Binding Lupus Maintenance Mediating Metabolic Diseases Molecular Mus N-Glycosylation Site N-terminal NCOA3 gene Nature Nephritis Patients Peptide Signal Sequences Phagocytes Phagocytosis Phosphatidylserines Physiological Play Prevention Process Production Proteins Publications Receptor Cell Reporting Research Resolution Role Signal Transduction Site Site-Directed Mutagenesis Surface Systemic Lupus Erythematosus T-Cell Activation Tertiary Protein Structure Testing Tissues Work acetyl-LDL cell injury chronic inflammatory disease cytokine glycosylation immune activation immune self tolerance in vivo lupus-like macrophage member new therapeutic target prevent protein protein interaction radioresistant receptor scavenger receptor systemic autoimmune disease trafficking uptake

项目摘要

Project Summary Efficient detection and clearance of apoptotic cells is essential in the maintenance of immune tolerance and tissue homeostasis. 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 the clearance of apoptotic debris have been identified. We previously identified the scavenger receptor expressed on endothelial cells-1 (SCARF1) as the receptor for apoptotic cells on dendritic cells via interactions with C1q/phosphatidylserine complexes on the dead cells (Ramirez-Ortiz et.al.; Nature Immunology). Loss of SCARF1 results in impaired uptake of apoptotic cells in vitro and in vivo, with accumulation of cell corpses in tissues and blood. Consequently, SCARF1-deficient mice develop lupus-like autoimmune disease. Our previous findings revealed that SCARF1 is a non-redundant efferocytosis receptor; however, additional work is needed to identify the mechanisms necessary for SCARF1-mediated removal of apoptotic cells and prevention of spontaneous autoimmunity in vivo. We hypothesize that SCARF1 plays an essential role in the physiological clearance of apoptotic debris, and that dysregulated or loss of SCARF1 expression on phagocytes leads to impaired AC uptake, loss of immune self-tolerance and development of autoimmunity. We propose to define the domains in SCARF1 that mediate recognition, signaling and removal of apoptotic cells and determine the relative contribution of SCARF1 in radioresistant cells vs hematopoietic cells. A comprehensive understanding of all the processes required for effective apoptotic cell removal can identify new targets not only for Lupus, but for many autoimmune, metabolic and infectious diseases.

项目摘要有效检测和凋亡细胞清除对于维持免疫是必不可少的耐受性和组织稳态。吞噬细胞负责去除垂死的细胞。但是，识别或吞噬细胞的缺陷会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全身性红斑狼疮（SLE）和吞噬细胞上的几种受体已经确定了负责清除凋亡碎屑的清除。我们以前已经确定在内皮细胞-1（Scarf1）上表达的清道夫受体作为凋亡的受体通过与死细胞上C1Q/磷脂酰丝氨酸复合物相互作用的树突状细胞上的细胞（Ramirez-Ortiz等人；自然免疫学）。疤痕1的损失导致吸收受损体外和体内凋亡细胞，组织和血液中细胞尸体的积累。因此，Scarf1缺陷小鼠会形成类似狼疮的自身免疫性疾病。我们的先前研究结果表明，Scarf1是一种非冗余的肿瘤受体。但是，其他需要工作以确定疤痕1介导的凋亡所必需的机制细胞和预防体内自发自身免疫。我们假设Scarf1播放在凋亡碎片的生理清除中的重要作用，并且失调或损失吞噬细胞上的Scarf1表达导致AC吸收受损，免疫自我耐受性丧失和自身免疫的发展。我们建议定义Scarf1中的域识别，信号和去除凋亡细胞，并确定辐射抗细胞中的疤痕1与造血细胞。对所有的全面理解有效凋亡细胞去除所需的过程不仅可以识别狼疮的新目标，但是对于许多自身免疫性，代谢和传染病。