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

项目摘要 有效地检测和清除凋亡细胞是维持免疫的关键 耐受性和组织动态平衡。吞噬细胞负责清除垂死的细胞； 然而，对凋亡细胞的识别缺陷或吞噬会导致慢性炎症。 和自身免疫性疾病。组织中凋亡细胞的积累与 自身免疫性疾病系统性红斑狼疮与吞噬细胞上的几种受体 已经确定了负责清除凋亡碎片的人。我们之前确定了 作为凋亡受体的内皮细胞清道夫受体-1(SCARF1)的表达 树突状细胞上的细胞与死亡细胞上的C1q/磷脂酰丝氨酸复合体相互作用 (Ramirez-Ortiz等人；自然免疫学)。SCARF1的缺失会导致对 在体外和体内均有细胞凋亡，组织和血液中有大量细胞积聚。 因此，SCARF1基因缺陷的小鼠发展为狼疮样自身免疫性疾病。我们以前的 研究结果表明，SCARF1是一种非多余的泡腾受体；然而，另一种 需要工作来确定SCARF1介导的去除细胞凋亡的必要机制 细胞与体内自发自身免疫的预防。我们假设SCARF1扮演 在生理上清除凋亡碎片中的重要作用，以及这种失调或丢失 吞噬细胞表达SCARF1导致AC摄取受损，免疫自我耐受性丧失 和自身免疫力的发展。我们建议在SCARF1中定义中介的域 识别、发送信号和清除凋亡细胞，并确定其相对贡献 SCARF1在辐射抵抗细胞和造血细胞中的表达。全面了解所有 有效去除凋亡细胞所需的过程不仅可以识别狼疮的新靶点， 但对于许多自身免疫、新陈代谢和传染病来说。

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.