MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis
MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis
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DOI：
10.1172/jci90520
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发表时间：
2017-02-01
影响因子：
15.9
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Cai, Bishuang;Thorp, Edward B.;Tabas, Ira
动脉粥样硬化血栓性血管疾病通常由一种独特类型的动脉粥样硬化病变触发，其表现出炎症消退受损的特征，特别是坏死核心和覆盖核心的保护性纤维帽变薄。斑块坏死的一个关键原因是损伤性巨噬细胞对凋亡细胞或巨噬细胞增多症的清除缺陷，但对缺陷性巨噬细胞增多症的潜在机制及其与动脉粥样硬化消退受损的可能联系尚不完全清楚。在这里，我们提供的证据表明，蛋白水解裂解的巨噬细胞胞浆细胞增多症受体c-Mer酪氨酸激酶（MerTK）减少胞浆细胞增多症，促进斑块坏死和缺陷的决议。在人颈动脉斑块中，MerTK裂解与斑块坏死和缺血症状的存在相关。此外，在脂饲LDL受体缺陷（Ldlr（-/-））小鼠（其骨髓细胞表达MerTK的裂解抗性变体）中，动脉粥样硬化病变表现出较高的巨噬细胞MerTK，较低水平的裂解产物可溶性Mer，改善的红细胞增多症，较小的坏死核心，较厚的纤维帽，以及促消退与促炎脂质介质的比例增加。这些发现提供了一个合理的分子-细胞机制，有助于在动脉粥样硬化进展过程中有缺陷的红细胞增多症，斑块坏死和受损的决议。
Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution. In human carotid plaques, MerTK cleavage correlated with plaque necrosis and the presence of ischemic symptoms. Moreover, in fat-fed LDL receptor-deficient (Ldlr(-/-)) mice whose myeloid cells expressed a cleavage-resistant variant of MerTK, atherosclerotic lesions exhibited higher macrophage MerTK, lower levels of the cleavage product soluble Mer, improved efferocytosis, smaller necrotic cores, thicker fibrous caps, and increased ratio of proresolving versus proinflammatory lipid mediators. These findings provide a plausible molecular-cellular mechanism that contributes to defective efferocytosis, plaque necrosis, and impaired resolution during the progression of atherosclerosis.