Role of SCARF1 in apoptotic cell clearance and prevention of autoimmunity

 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内稳态至关重要。专业吞噬细胞负责清除死亡细胞；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。凋亡细胞在组织中的聚集与自身免疫性疾病系统性红斑狼疮(SLE)有关，已发现吞噬细胞上的几种受体负责清除凋亡细胞。我们最近发现，清道夫受体SCARF1在细胞凋亡的感知和吞噬过程中发挥着重要作用。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，磷脂酰丝氨酸是一种主要的Eat Me信号，从濒死细胞的细胞膜内转移到外叶。Scarf1基因缺陷会导致组织中凋亡细胞的聚集和狼疮样自身免疫性疾病的自发发展，并产生染色质自身抗体，免疫细胞的异常激活，皮炎和肾炎。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的几个主要空白；然而，还需要进一步的工作来确定SCARF1介导的凋亡细胞清除和体内自发自身免疫预防所必需的机制。由于细胞凋亡的清除需要体内大量的受体和桥接分子，我们假设免疫系统已经形成了故障保护机制，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，用于清除死亡细胞，以维持耐受和防止自身免疫。为了验证这些假说，我们将：(1)确定Scarf1缺乏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、吞噬和信号传递的结构域。了解离散细胞群体使用SCARF1吞噬凋亡细胞和预防炎症的机制，应该能够通过在特定细胞亚群中靶向SCARF1来设计治疗自身免疫性疾病的新型定制药物。

 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.