Role of Mast Cells in Atherosclerosis

描述（由申请人提供）：肥大细胞（MC）被认为是通过释放胞质颗粒残留物引发过敏反应的重要效应细胞。以前的研究表明，MC也参与白细胞募集，泡沫细胞形成，平滑肌细胞增殖，T细胞迁移和激活，所有必要的动脉粥样硬化，炎症性疾病涉及复杂的细胞-细胞相互作用，细胞因子的产生，和免疫反应。在人类动脉粥样硬化病变中检测到增加的MC积累表明它们参与动脉粥样硬化形成。在粥样硬化的肩部，MC密度最高，在那里它们易于侵蚀和破裂，但在纤维帽和未受影响的椎间盘中几乎不出现。然而，目前尚不清楚动脉粥样硬化中MC的积累是否直接影响动脉粥样硬化的发生，或者仅仅是许多标志之一。我们最近的初步研究表明，MC直接参与动脉粥样硬化的形成。在小鼠中，病变MC的积累与动脉粥样硬化形成的进展相关。在致动脉粥样硬化饮食26周后，MC的缺乏使动脉粥样硬化形成受损>50%。减少动脉粥样硬化在MC-裸小鼠可以完全恢复重建的小鼠与野生型MC，但不是白细胞介素-6缺陷的MC。此外，用MC去稳定剂激活MC使动脉粥样硬化形成增加近30%。缺乏对这些观察结果的机制解释导致了一个中心假设，即MC通过释放炎症介质促进白细胞募集和迁移、巨噬细胞泡沫细胞形成、平滑肌细胞增殖和迁移、淋巴细胞活化和基质降解蛋白酶表达来直接影响动脉粥样硬化形成。我们提出了三个具体的目标来验证这一假设，通过检查MC的缺乏是否会影响动脉粥样硬化的发生，以及我们是否可以通过调节MC激活来控制动脉粥样硬化;识别MC使用哪些分子来影响血管壁重塑;并测试MC如何影响体外其他血管细胞; MC的缺乏是否会影响其他造血细胞的生物学;以及体内MC迁移和募集所需的介质。总之，这些线的实验应提供在体外和体内的证据，是否动脉粥样硬化的发病机制需要MC功能，并导致详细的机制解释如何MC可能参与这种常见的血管疾病的发病机制。

DESCRIPTION (provided by applicant): Mast cells (MCs) are recognized as essential effector cells in the elicitation of allergic response by releasing cytoplasmic granule remnants. Previous studies suggest that MCs also participate in leukocyte recruitment, foam cell formation, smooth muscle cell proliferation, and T cell migration and activation, all essential for atherosclerosis, an inflammatory disease involving sophisticated cell-cell interaction, cytokine production, and immune responses. Detection of increased MC accumulation in human atherosclerotic lesions suggests their participation in atherogenesis. MCs appear in highest density in atheroma shoulder regions, where they are prone to erosion and rupture, but appear only scarcely in the fibrous caps and unaffected aortae. However, it remains uncertain whether accumulation of MCs in atheromata directly affects atherogenesis or is merely one of the many hallmarks. Our recent preliminary studies suggest that MCs participate directly in atherogenesis. In mice, the accumulation of lesion MCs correlated with the progression of atherogenesis. Absence of MCs impaired atherogenesis by >50% after 26 weeks of an atherogenic diet. Reduced atheromata in MC-null mice can be fully restored by reconstituting the mice with wild-type MCs but not interleukin-6-deficient MCs. Furthermore, MC activation with MC destabilizer enhanced atherogenesis by nearly 30%. Lack of mechanistic explanations for these observations led to a central hypothesis that MCs directly affect atherogenesis by releasing inflammatory mediators to promote leukocyte recruitment and migration, macrophage foam cell formation, smooth muscle cell proliferation and migration, lymphocyte activation, and matrix-degrading protease expression. We propose three specific aims to test this hypothesis by examining whether absence of MCs affects atherogenesis and whether we can control atherosclerosis by regulating MC activation; identifying which molecules MCs use to influence vascular wall remodeling; and testing how MCs affect other vascular cells in vitro; whether absence of MCs affects the biology of other hematopoietic cells; and which mediators are required for MC migration and recruitment in vivo. Together, these lines of experiments should provide both in vitro and in vivo evidence of whether the pathogenesis of atherosclerosis requires MC functions, and result in detailed mechanistic explanations of how MCs might participate in the pathogenesis of this common vascular disorder.