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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.

项目摘要凋亡细胞的有效检测和清除在维持免疫调节中是必不可少的。耐受性和组织稳态。吞噬细胞负责清除垂死细胞; 然而，识别或吞噬凋亡细胞的缺陷可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肿瘤的发生有关。自身免疫性疾病系统性红斑狼疮（SLE）和吞噬细胞上的几种受体负责清除凋亡碎片。我们之前发现内皮细胞上表达的清道夫受体-1（SCARF 1）作为细胞凋亡的受体，通过与死细胞上的C1 q/磷脂酰丝氨酸复合物的相互作用，（Ramirez-Ortiz等人; Nature Immunology）。SCARF 1的缺失导致在体外和体内的凋亡细胞，随着组织和血液中细胞尸体的积累。因此，SCARF 1缺陷小鼠发展成狼疮样自身免疫性疾病。我们以前的研究结果显示，SCARF 1是一种非冗余的红细胞增多症受体;然而，需要进行工作来确定SCARF 1介导的细胞凋亡清除所必需的机制，细胞和预防体内自发性自身免疫。我们假设SCARF 1在在凋亡碎片的生理清除中起重要作用，吞噬细胞上SCARF 1表达的降低导致AC摄取受损，免疫自身耐受性丧失，和自身免疫的发展。我们建议定义SCARF 1中介导识别，信号传导和去除凋亡细胞，并确定相对贡献抗辐射细胞与造血细胞中的SCARF 1。全面了解所有有效去除凋亡细胞所需的过程不仅可以鉴定狼疮的新靶点，但对于许多自身免疫性、代谢性和感染性疾病也是如此。