Zheng Qianqian, Duan Liangwei, Lou Yunwei, Chao Tianzhu, Guo Guo, Lu Liaoxun, Zhang Hongxia, Zhao Yucong, Liang Yinming, Wang Hui
Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, People's Republic of China; Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People's Republic of China.
Laboratory of Mouse Genetics, Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, People's Republic of China.
Atherosclerosis. 2021 Oct 16;337:42-52. doi: 10.1016/j.atherosclerosis.2021.10.010.
Atherosclerosis, a progressive inflammatory disease characterized by elevated inflammation and lipid accumulation in the aortic endothelium, arises in part from the infiltration of inflammatory cells into the vascular wall. However, it is not fully defined how inflammatory cells, especially macrophages, affect the pathogenesis of atherosclerosis. Schlafen4 (Slfn4) mRNA is remarkably upregulated upon ox-LDL stimulation in macrophages. Nonetheless, the role of Slfn4 in foam cell formation remains unclear.
To determine whether and how Slfn4 regulates lesion macrophage function during atherosclerosis，we engineered ApoESlfn4 double-deficient mice on an ApoE background and evaluated the deficiency of Slfn4 expression in atherosclerotic lesion formation in vivo.
Our results demonstrate that total absence of SLFN4 and the bone marrow-restricted deletion of Slfn4 in ApoE mice remarkably diminish inflammatory cell numbers within arterial plaques as well as limit development of atherosclerosis in moderate hypercholesterolemia condition. This is linked to a marked reduction in the expression of proinflammatory cytokines, the generation of the reactive oxygen species (ROS) and the apoptosis of cells. Furthermore, the activation of MAPKs and apoptosis signaling pathways is compromised in the absence of Slfn4.
These findings demonstrate a novel role of Slfn4 in modulating vascular inflammation and atherosclerosis, highlighting a new target for the related diseases.
动脉粥样硬化是一种渐进性炎症性疾病，其特征为主动脉内皮炎症加剧和脂质蓄积，部分原因是炎性细胞浸润至血管壁。然而，炎性细胞尤其是巨噬细胞如何影响动脉粥样硬化的发病机制尚未完全明确。巨噬细胞经氧化型低密度脂蛋白（ox-LDL）刺激后， Schlafen4（Slfn4）mRNA显著上调。尽管如此，Slfn4在泡沫细胞形成中的作用仍不清楚。
为了确定Slfn4是否以及如何在动脉粥样硬化过程中调节病变巨噬细胞功能，我们构建了载脂蛋白E（ApoE）背景的ApoESlfn4双缺陷小鼠，并在体内评估了Slfn4表达缺失对动脉粥样硬化病变形成的影响。
我们的结果表明，ApoE小鼠中完全缺乏SLFN4以及骨髓限制性缺失Slfn4，可显著减少动脉斑块内的炎性细胞数量，并在中度高胆固醇血症条件下限制动脉粥样硬化的发展。这与促炎细胞因子表达的显著降低、活性氧（ROS）的产生以及细胞凋亡有关。此外，在缺乏Slfn4的情况下，丝裂原活化蛋白激酶（MAPKs）和凋亡信号通路的激活受到损害。
这些发现证明了Slfn4在调节血管炎症和动脉粥样硬化中的新作用，为相关疾病提供了一个新的靶点。
