Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.
Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.
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DOI：
10.1161/atvbaha.116.308014
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Alexandropoulos K
中科院分区：
文献类型：
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作者：
Herbin O;Regelmann AG;Ramkhelawon B;Weinstein EG;Moore KJ;Alexandropoulos K
与动脉粥样硬化相关的慢性炎症是由脂质沉积引起的，随后白细胞聚集到动脉壁。我们以前表明，造血细胞特异性衔接蛋白Chat-H/SHEP 1调节淋巴细胞粘附和迁移。在这项研究中，我们分析了Chat-H在动脉粥样硬化发展中的作用。通过在低密度脂蛋白受体（Ldlr）缺陷小鼠中进行Chat-H缺陷骨髓移植，我们发现Chat-H调节动脉粥样硬化斑块的形成。造血细胞中Chat-H缺乏与斑块复杂性降低和病变中白细胞减少相关，而骨髓特异性Chat-H缺失足以提供动脉粥样硬化保护。Chat-H缺乏导致经典Ly 6chigh和非经典Ly 6clow单核细胞向斑块的募集减少，这伴随着血液中两种单核细胞亚群的数量增加。这与Chat-H缺陷型Ly 6chigh和Ly 6clow单核细胞在体外与VCAM-1的粘附缺陷有关，并损害了荧光珠负载的单核细胞向动脉粥样硬化斑块的浸润。相比之下，Chat-H对CX 3CL 1和CCR 1/CCR 5依赖的单核细胞迁移无影响。我们的研究结果突出了Chat-H作为一种关键蛋白，通过控制单核细胞粘附和招募斑块来调节动脉粥样硬化的发展，并确定了一种可用于治疗动脉粥样硬化的新靶点。
The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic-cell-specific adaptor protein Chat-H/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development. Using Chat-H deficient bone marrow transplantation in low density lipoprotein receptor (Ldlr)-deficient mice, we found that Chat-H regulated atherosclerotic plaque formation. Chat-H deficiency in hematopoietic cells associated with lower plaque complexity and fewer leukocytes in the lesions, whereas myeloid-specific deletion of Chat-H was sufficient for conferring atheroprotection. Chat-H deficiency resulted in reduced recruitment of classical Ly6chigh and non-classical Ly6clow monocytes to the plaques, which was accompanied by increased numbers of both monocyte subsets in the blood. This associated with defective adhesion of Chat-H-deficient Ly6chigh and Ly6clow monocytes to VCAM-1 in vitro, and impaired infiltration of fluorescent-bead-loaded monocytes to atherosclerotic plaques. In contrast, Chat-H was dispensable for CX3CL1 and CCR1/CCR5-dependent migration of monocytes. Our findings highlight Chat-H as a key protein that regulates atherosclerosis development by controlling monocyte adhesion and recruitment to the plaques and identify a novel target that may be exploited for treating atherosclerosis.