Testing the tyrosine phosphatase SHP-2 as a novel brake on efferocytosis

项目摘要/摘要 每天，我们周转数十亿个被吞噬细胞移除的凋亡细胞，例如 巨噬细胞。细胞死亡和吞噬清除过程对维持体内平衡至关重要， 与许多疾病的病理有关。随着动脉粥样硬化斑块的发展，单核细胞来源的巨噬细胞渗入 血管壁可以清除富含胆固醇的脂蛋白和细胞碎片，但这些富含脂质的巨噬细胞最终会 由于长期暴露在空气中，导致吞噬功能受损，并发生细胞凋亡(一种细胞死亡形式) 对炎性刺激。未清除的凋亡细胞最终进展为继发性坏死，并随着它们的血浆 膜变得通透，细胞内的内容被释放到周围的微环境中，进一步 刺激炎症反应。晚期动脉粥样硬化斑块有大的炎性坏死核心 随着未清除的死亡细胞和碎片在血管壁内堆积而发展。因此，需要使用模式来增强 清除死亡细胞，促进晚期斑块内炎症的消退。除了专业之外 吞噬细胞(如在动脉粥样硬化病变中受损的巨噬细胞)、非专业性吞噬细胞也 存在并参与清除过程，如消化道和肺内的上皮细胞，或间充质细胞 胚胎肢体发育过程中的细胞。这些非专业吞噬细胞在维持 动态平衡，然而非专业吞噬细胞帮助清除动脉粥样硬化斑块的潜力已经 没有被处理过。根据我们的初步研究，酪氨酸磷酸酶SHP-2的缺失会增强 非专业性吞噬细胞如成纤维细胞在体外清除凋亡细胞。我们建议进一步测试 SHP-2在清除死亡细胞中的作用及其机制(S)和免疫学 这种表型背后的反应。此外，我们建议测试SHP-2在调节动脉粥样硬化中的作用 体内斑块清除。了解SHP-2在调节不同类型细胞吞噬过程中的作用 处于动态平衡和动脉粥样硬化斑块中的吞噬细胞将提供重要的治疗机会 动脉硬化。

PROJECT SUMMARY/ABSTRACT On a daily basis, we turnover billions of apoptotic cells that are removed by phagocytic cells, such as macrophages. The processes of cell death and phagocytic clearance are vital to maintaining homeostasis and are related to many disease pathologies. As atherosclerotic plaques develop, monocyte-derived macrophages infiltrate vessel walls to remove cholesterol-rich lipoproteins and cellular debris, but these lipid-laden macrophages eventually become impaired in their phagocytic activity and undergo apoptosis (a form of cell death) due to prolonged exposure to inflammatory stimuli. Uncleared apoptotic cells eventually progress to secondary necrosis, and as their plasma membranes become permeabilized, intracellular contents are released into the surrounding microenvironment, further stimulating an inflammatory response. Advanced atherosclerotic plaques with large, inflammatory necrotic cores develop as uncleared dead cells and debris accumulate within vessel walls. Thus, modalities are needed to enhance the clearance of dead cells and promote inflammation resolution within advanced plaques. In addition to professional phagocytes (such as macrophages, which are impaired in atherosclerotic lesions), non-professional phagocytes also exist and participate in the clearance process, such as epithelial cells in the digestive tract and lung, or mesenchymal cells during embryonic limb development. These non-professional phagocytes can play vital roles in maintaining homeostasis, yet the potential of non-professional phagocytes to help in the clearance of atherosclerotic plaques has not been addressed. Based on our preliminary studies, loss of the tyrosine phosphatase, SHP-2, enhances the clearance of apoptotic cells by non-professional phagocytes such as fibroblasts in vitro. We propose to further test the role of SHP-2 as a novel brake on the clearance of dead cells, and define the mechanism(s) and immunologic responses underlying this phenotype. Further, we propose to test the role of SHP-2 in modulating atherosclerotic plaque clearance in vivo. Understanding the role of SHP-2 in regulating the phagocytic process by different types of phagocytes at homeostasis and in atherosclerotic plaques will provide important therapeutic opportunities for atherosclerosis.