Role of Vimentin, sPLA2 and LysoPC in Autoimmune Disease

描述(由申请人提供)： 细胞凋亡是细胞程序性死亡的一种形式，在器官和组织重塑以及造血细胞的发育和成熟等过程中是必不可少的。凋亡细胞的清除是防止自身免疫反应的关键，隔离抗原在细胞凋亡过程中暴露，并主要由巨噬细胞/单核细胞系的吞噬细胞介导。在发生吞噬作用之前，巨噬细胞必须首先通过趋化作用被招募到凋亡细胞中。 磷脂酶A2(PLA2)催化的反应产物能诱导单核细胞趋化。一些研究人员发现，在细胞凋亡过程中，细胞内存在一种钙非依赖性的磷脂酶A2，参与这些产物的产生。然而，最近的一份报告表明，分泌组Ila sPLA2结合到凋亡细胞的表面。这个sPLA2池的“受体”是波形蛋白的杆状结构域，波形蛋白是一种中间细丝蛋白，在细胞发生凋亡时暴露出来。特定的半胱氨酸天冬氨酸酶导致中间丝网络的解体先于核解体，这是发生在凋亡细胞中的最初事件之一。基于这些观察，我们假设Vimentin暴露在凋亡细胞上会捕获一池具有催化活性的sPLA2，然后sPLA2产生生物活性脂质并诱导巨噬细胞趋化。为了验证这一假设，我们将进一步表征波形蛋白和sPLA2之间的相互作用，特别是容易水解质膜外层小叶中的两性离子磷脂的V族酶。我们还将进行实验，以确定波形蛋白相关的sPLA2池是否增强巨噬细胞对凋亡细胞的募集。总之，这些研究应该为sPLA2的一种新功能提供洞察力，并可能提出新的方法来增强对凋亡细胞的清除，从而防止自身免疫反应。

DESCRIPTION (provided by applicant): Apoptosis is a form of programmed cell death that is essential in such processes as organ and tissue remodeling and the development and maturation of hematopoietic cells. The clearance of apoptotic cells is essential to prevent autoimmune responses to sequestered antigens that are exposed during the process of apoptosis and is largely mediated by phagocytes of the macrophage/monocyte lineage. Before phagocytosis can occur, macrophages must first be recruited to the apoptotic cells through chemotaxis. Products of the reaction catalyzed by the phospholipases A2 (PLA2) have been shown to induce monocyte chemotaxis. Some investigators have implicated a cytosolic calcium-independent PLA2 in the production of these products during apoptosis. However, a recent report suggests that secreted group Ila sPLA2 binds to the surfaces of apoptotic cells. The "receptor" for this pool of sPLA2 is the rod domain of vimentin, an intermediate filament protein that is exposed when cells undergo apoptosis. Disintegration of the intermediate filament network by specific caspases precedes nuclear disintegration and is one of the initial events that occurs in apoptotic cells. Based on these observations, we hypothesize that the exposure of vimentin on apoptotic cells traps a pool of catalytically active sPLA2 that then generates the bioactive lipids and induce macrophage chemotaxis. To test this hypothesis, we will further characterize the interactions between vimentin and the sPLA2s, in particular the group V enzyme that readily hydrolyzes the zwitterionic phospholipids in the outer leaflet of the plasma membrane. We will also perform experiments to determine if the vimentin-associated pool of sPLA2 enhances the recruitment of macrophages to apoptotic cells. All together, these studies should provide insights into a novel function of sPLA2 and may suggest new ways to enhance the clearance of apoptotic cells and thereby prevent autoimmune responses.