Clearance of Apoptotic Cells

描述（由申请方提供）：本提案的目的是确定Mer在巨噬细胞清除凋亡细胞中的生物学相关性，并描述巨噬细胞清除凋亡细胞的识别、吞噬作用和抗炎后果的机制。对于凋亡细胞的识别和更新机制以及由凋亡细胞触发的信号转导途径仍然知之甚少。假设Mer/Tyro 3/Axl受体酪氨酸激酶促进凋亡细胞的吞噬作用。我们的初步（体内和体外）研究强烈表明，Mer，一种受体酪氨酸激酶表达的巨噬细胞，参与介导的凋亡细胞的清除，并出现调节抗炎反应。具有突变的Mer胞质信号传导激酶结构域（merkd）的小鼠具有在抑制促炎细胞因子（如TNF-α）方面有缺陷的巨噬细胞，并且在吞噬凋亡细胞方面有缺陷。此外，我们推测这种缺陷与临床相关，因为merkd小鼠产生升高的血清IgM自身抗体，肾脏显示病理学。事实上，越来越多的证据表明，凋亡细胞可以促进自身免疫性疾病的发病机制，并且凋亡细胞的高负荷可以提供自身抗体产生的重要途径，因为它与SLE有关。研究凋亡细胞的识别和清除过程可能为控制炎症和自身免疫性疾病提供见解。为了实现这一目标，我们建议通过新的受体酪氨酸激酶，Axl，Mer和Tyro 3在巨噬细胞上表达，在体内和体外的凋亡细胞的清除过程中所涉及的调查。

DESCRIPTION (provided by applicant): The purpose of this proposal is to determine the biological relevance of Mer in the clearance of apoptotic cells by macrophages and to delineate in a mechanism that would account for the recognition, phagocytosis and anti-inflammatory consequence of clearing apoptotic cells by macrophages. A mechanism for recognition and update of apoptotic cells and the signal transduction pathway(s) triggered by apoptotic cells is still poorly understood. The hypothesis is Mer/Tyro3/Axl Receptor Tyrosine Kinases facilitate phagocytosis of apoptotic cells. Our preliminary (in vivo and in vitro) studies strongly suggest that Mer, a receptor tyrosine kinase expressed on macrophages, is involved in mediating the clearance of apoptotic cells and appears to modulate an anti-inflammatory response. Mice with a mutated Mer cytoplasmic signaling kinase domain (merkd) have macrophages that are defective in suppressing pro-inflammatory cytokines such as TNF-¿ and are defective in phagocytizing apoptotic cells. Furthermore, we presume that this defect is clinically relevant in that merkd mice produce elevated serum IgM autoantibodies and kidney shows pathology. Indeed, evidence is accruing that apoptotic cells can contribute to pathogenesis of autoimmune diseases, and that a high burden of apoptotic cells may provide an important route to autoantibody production as it has been implicated in SLE. Investigating the process involved in recognition and clearance of apoptotic cells may provide insights towards controlling inflammation and autoimmune disorders. Towards this goal, we propose to investigate the process involved in the clearance of apoptotic cells both in vivo and in vitro through novel receptor tyrosine kinases, Axl, Mer, and Tyro3 expressed on macrophages.