Role of Mast Cells in Atherosclerosis

描述(申请人提供)：肥大细胞(MC)被认为是通过释放细胞质颗粒残留物而引起过敏反应的基本效应细胞。先前的研究表明，MC还参与白细胞募集、泡沫细胞的形成、平滑肌细胞的增殖以及T细胞的迁移和激活，这些都是动脉粥样硬化所必需的，动脉粥样硬化是一种涉及复杂的细胞-细胞相互作用、细胞因子产生和免疫反应的炎症性疾病。检测到MC在人类动脉粥样硬化病变中积聚增加，表明它们参与了动脉粥样硬化的形成。MCs在易受侵蚀和破裂的动脉粥样硬化性肩部密度最高，但仅在纤维帽和未受影响的主动脉中很少出现。然而，目前尚不确定动脉粥样硬化中MC的积聚是直接影响动脉粥样硬化的形成，还是仅仅是众多标志之一。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的进展相关。在26周的致动脉粥样硬化饮食后，缺乏MC可使动脉粥样硬化减少50%。通过重组野生型MC而不是白介素6缺乏MC的小鼠，MC缺失小鼠减少的动脉粥样硬化可以完全恢复。此外，用MC去稳定剂激活MC可使动脉粥样硬化的形成增加近30%。由于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通过释放炎症介质来促进白细胞的募集和迁移、巨噬细胞泡沫细胞的形成、平滑肌细胞的增殖和迁移、淋巴细胞的激活和基质降解酶的表达，从而直接影响动脉粥样硬化的形成。我们提出了三个具体的目标来验证这一假说：检测MC的缺失是否会影响动脉粥样硬化的形成，以及我们是否可以通过调节MC的激活来控制动脉粥样硬化；确定MC使用哪些分子来影响血管壁重建；以及测试MC在体外如何影响其他血管细胞；MC的缺失是否影响其他造血细胞的生物学；以及MC在体内的迁移和募集需要哪些介体。总之，这些实验应该提供体外和体内证据，证明动脉粥样硬化的发病机制是否需要MC功能，并对MC如何参与这种常见血管疾病的发病机制做出详细的机制解释。

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.