Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis.
Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis.
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DOI：
10.1253/circj.cj-16-0924
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Yancey PG
中科院分区：
文献类型：
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作者：
Linton MF;Babaev VR;Huang J;Linton EF;Tao H;Yancey PG
巨噬细胞凋亡和巨噬细胞清除死亡细胞的能力（称为巨噬细胞增多）是动脉粥样硬化病变进展和斑块稳定性的关键决定因素。环境应激启动内质网应激并激活未折叠蛋白反应。未解决的ER应激与UPR的激活启动细胞凋亡。由于PI 3 K/Akt通路的活性，巨噬细胞对凋亡刺激具有抗性。巨噬细胞表达3种Akt亚型：Akt 1、Akt 2和Akt 3，它们是不同但同源基因的产物。Akt在动脉粥样硬化形成中显示出亚型特异性作用，其随不同的血管细胞类型而变化。巨噬细胞Akt 2的缺失促进抗炎M2表型并减少动脉粥样硬化。然而，Akt同种型在细胞凋亡方面是多余的。c-Jun NH 2-末端激酶（JNK）是UPR的促凋亡效应子，并且JNK 1同种型对抗抗凋亡Akt信号传导。造血细胞中JNK 1的缺失保护巨噬细胞免于凋亡并加速早期动脉粥样硬化。IκB激酶α（IKKα，丝氨酸/苏氨酸蛋白激酶家族的成员）在巨噬细胞中mTORC 2介导的Akt信号传导中起重要作用，IKKα缺乏降低巨噬细胞存活并抑制早期动脉粥样硬化。胞饮作用涉及受体、桥接分子和凋亡细胞配体的相互作用。I型B类清道夫受体是动脉粥样硬化中通过Src/PI 3 K/Rac 1途径介导巨噬细胞吞噬的关键介质。解决炎症的激动剂提供了有希望的治疗潜力，以促进红细胞增多症和预防动脉粥样硬化临床事件。
Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes. Akt displays isoform-specific effects on atherogenesis, which vary with different vascular cell types. Loss of macrophage Akt2 promotes the anti-inflammatory M2 phenotype and reduces atherosclerosis. However, Akt isoforms are redundant with regard to apoptosis. c-Jun NH2-terminal kinase (JNK) is a pro-apoptotic effector of the UPR, and the JNK1 isoform opposes anti-apoptotic Akt signaling. Loss of JNK1 in hematopoietic cells protects macrophages from apoptosis and accelerates early atherosclerosis. IκB kinase α (IKKα, a member of the serine/threonine protein kinase family) plays an important role in mTORC2-mediated Akt signaling in macrophages, and IKKα deficiency reduces macrophage survival and suppresses early atherosclerosis. Efferocytosis involves the interaction of receptors, bridging molecules, and apoptotic cell ligands. Scavenger receptor class B type I is a critical mediator of macrophage efferocytosis via the Src/PI3K/Rac1 pathway in atherosclerosis. Agonists that resolve inflammation offer promising therapeutic potential to promote efferocytosis and prevent atherosclerotic clinical events.