Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption
Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption
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DOI：
10.1016/j.bbalip.2019.04.001
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发表时间：
2019-07-01
影响因子：
4.8
通讯作者：
Legrand-Poels, Sylvie
中科院分区：
文献类型：
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作者：
Gianfrancesco, Marco A.;Dehairs, Jonas;Legrand-Poels, Sylvie
NLRP3炎症小体在西方饮食诱导的全身炎症中起着关键作用，最近被证明在髓系细胞中介导了持久的训练性免疫。饱和脂肪酸(SFA)是一种无菌触发物，能够诱导巨噬细胞中NLRP3炎症体的组装，导致IL-1β的分泌，而不饱和脂肪酸(UFA)则阻止SFAs介导的NLRP3激活。与以前使用脂多糖诱导的骨髓来源的巨噬细胞的研究不同，我们没有看到任何ROS或IRE-1α参与SFAs介导的人类单核细胞来源的巨噬细胞的NLRP3激活。相反，我们发现SFA需要进入细胞并被激活为酰基辅酶A，从而导致人巨噬细胞中NLRP3的激活。然而，它们的β氧化作用是可有可无的。相反，在不饱和脂肪酸存在的情况下，它们被引导到磷脂，但被重定向到含有三酰甘油的脂滴。脂质体学分析和Laurdan荧光实验表明，SFAs诱导与膜流动性丧失相关的磷脂酰胆碱(PC)的急剧饱和，这两种情况都被UFAs抑制。PC合成中的关键酶CCTα的沉默阻止了SFA介导的NLRP3激活，表明PC从头合成的关键作用。这种SFA诱导的膜重塑促进了质膜Na，K-ATPase的破坏，促使K+外流是NLRP3激活所必需的和充分的。这项工作为干预西方饮食相关疾病开辟了新的治疗途径，例如那些针对甘油脂途径的疾病。
NLRP3 inflammasome plays a key role in Western diet induced systemic inflammation and was recently shown to mediate long-lasting trained immunity in myeloid cells. Saturated fatty acids (SFAs) are sterile triggers able to induce the assembly of the NLRP3 inflammasome in macrophages, leading to IL-1 beta secretion while unsaturated ones (UFAs) prevent SFAs-mediated NLRP3 activation. Unlike previous studies using LPS-primed bone marrow derived macrophages, we do not see any ROS or IRE-1 alpha involvement in SFAs-mediated NLRP3 activation in human monocytes-derived macrophages. Rather we show that SFAs need to enter the cells and to be activated into acyl-CoA to lead to NLRP3 activation in human macrophages. However, their beta-oxidation is dispensable. Instead, they are channeled towards phospholipids but redirected towards lipid droplets containing triacylglycerol in the presence of UFAs. Lipidomic analyses and Laurdan fluorescence experiments demonstrate that SFAs induce a dramatic saturation of phosphatidylcholine (PC) correlated with a loss of membrane fluidity, both events inhibited by UFAs. The silencing of CCT alpha, the key enzyme in PC synthesis, prevents SFA-mediated NLRP3 activation, demonstrating the essential role of the de novo PC synthesis. This SFA-induced membrane remodeling promotes a disruption of the plasma membrane Na, K-ATPase, instigating a K+ efflux essential and sufficient for NLRP3 activation. This work opens novel therapeutic avenues to interfere with Western diet-associated diseases such as those targeting the glycerolipid pathway.