Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation
Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation
复制标题
Sirtuin 3诱导巨噬细胞自噬调节NLRP3炎症小体激活
DOI：
10.1016/j.bbadis.2017.12.027
复制
发表时间：
2018-03-01
影响因子：
6.2
通讯作者：
Shen, Weili
中科院分区：
文献类型：
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作者：
Liu, Penghao;Huang, Gaojian;Shen, Weili
单核细胞或巨噬细胞的自噬缺陷可能导致NLRP 3炎性体活化并引起血管代谢性炎症。然而，自噬反应的启动机制仍然不清楚。Sirtuin 3（SIRT 3）是一种NAD依赖性脱乙酰酶，对代谢状态敏感并介导适应反应。在这项研究中，我们研究了SIRT 3介导的自噬在调节NLRP 3炎性小体激活中的作用。我们确定，自噬的抑制和NLRP 3炎性体的激活伴随着来自肥胖人的外周血单核细胞和棕榈酸酯处理的THP-1细胞中SIRT 3水平的降低。此外，我们证明了SIRT 3可以与ATG 5形成分子复合物，而SIRT 3过表达改变了内源性ATG 5的乙酰化。ATG 5乙酰化抑制自噬体成熟并诱导NLRP 3炎性体活化。与此同时，SIRT 3在THP-1细胞中的过表达减少了棕榈酸诱导的线粒体活性氧的产生，恢复了自噬，并减弱了NLRP 3炎性小体的激活。人主动脉内皮细胞（HAECs）与巨噬细胞条件培养基（MCM）孵育诱导HAEC表达血管细胞粘附分子-1，细胞间粘附分子1，α-平滑肌肌动蛋白和胶原蛋白-1。MCM的作用可以通过加入中和性抗IL-1 β抗体或SIRT 3的过表达来逆转。与此一致，正面分析显示，患有急性血小板血症的SIRT 3（-/-）小鼠中α-SMC阳性内皮细胞显著增加。综上所述，这些发现揭示了SIRT 3缺陷型巨噬细胞显示出受损的自噬和加速的NLRP 3炎性体活化和内皮功能障碍。
Defective autophagy of monocytes or macrophages might result in NLRP3 inflammasome activation and cause vascular metabolic inflammation. However, the mechanism underlying the initiation of the autophagy response to hyperlipidaemia remains unclear. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is sensitive to the metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated autophagy in regulating NLRP3 inflammasome activation. We determined that the inhibition of autophagy and the activation of the NLRP3 inflammasome were concomitant with reduced SIRT3 levels both in peripheral blood monocytes from obese humans and in palmitate-treated THP-1 cells. Furthermore, we demonstrated that SIRT3 could form a molecular complex with ATG5, while SIRT3 overexpression altered the acetylation of endogenous ATG5. ATG5 acetylation inhibited autophagosome maturation and induced NLRP3 inflammasome activation. In parallel, SIRT3 overexpression in THP-1 cells decreased the palmitate-induced generation of mitochondrial reactive oxygen species, restored autophagy, and attenuated NLRP3 inflammasome activation. The incubation of human aortic endothelial cells (HAECs) with macrophage-conditioned medium (MCM) induced HAEC expression of vascular cell adhesion molecule-1, intercellular adhesion molecule 1, alpha-smooth muscle actin, and collagen-1. The effect of MCM could be reversed by the addition of neutralizing anti-IL-1 beta antibody or the overexpression of SIRT3. Consistent with this, en face analyses displayed a marked increase in alpha-SMC-positive endothelial cells in SIRT3(-/-) mice with acute hyperlipidaemia. Taken together, these findings revealed that SIRT3-deficient macrophages displayed impaired autophagy and accelerated NLRP3 inflammasome activation and endothelial dysfunction.