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稳态至关重要。专职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自身免疫性疾病系统性红斑狼疮（SLE）有关，并且已经鉴定了吞噬细胞上负责凋亡细胞清除的几种受体。我们最近发现清道夫受体SCARF 1在凋亡细胞的感知和吞噬中起重要作用。树突状细胞使用SCARF 1通过与暴露的磷脂酰丝氨酸结合的C1 q捕获凋亡细胞，这是一种主要的进食信号，在垂死细胞上从细胞膜的内叶易位到外叶。小鼠Scarf 1缺陷导致组织中凋亡细胞的积累和狼疮样自身免疫性疾病的自发发展，产生针对染色质的自身抗体、异常免疫细胞活化、皮炎和肾炎。我们以前的研究结果填补了我们对凋亡细胞清除和自身免疫调节的理解中的几个主要空白;然而，需要更多的工作来确定SCARF 1介导的凋亡细胞清除和预防体内自发性自身免疫所需的机制。由于凋亡细胞的清除需要大量的受体和桥接分子在体内，我们假设，免疫系统已经开发出故障安全机制，涉及多种受体和桥接蛋白表达的不同类型的细胞存在于特定组织中的死亡细胞的去除，以保持耐受性和防止自身免疫。为了验证这些假设，我们将（1）确定Scarf 1缺陷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SCARF 1，CD 36和C1 q对凋亡细胞清除和预防自身免疫性疾病的相对贡献;（3）确定SCARF 1中介导凋亡细胞识别，吞噬作用和信号传导的结构域。了解离散细胞群使用SCARF 1吞噬凋亡细胞和预防炎症的机制，应该能够通过靶向特定细胞亚群中的SCARF 1来设计针对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.