Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and Oxidative Phosphorylation.
Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and Oxidative Phosphorylation.
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DOI：
10.1161/atvbaha.120.315758
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Fredman G
中科院分区：
文献类型：
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作者：
Hosseini Z;Marinello M;Decker C;Sansbury BE;Sadhu S;Gerlach BD;Bossardi Ramos R;Adam AP;Spite M;Fredman G
斑块坏死是动脉粥样硬化消退缺陷的一个关键特征。最近的证据表明坏死性凋亡促进斑块坏死，因此我们试图确定坏死性凋亡细胞（NC）如何影响斑块中的消退程序。为了研究坏死性凋亡在晚期动脉粥样硬化中的作用，我们使用缺乏Mlkl（坏死性凋亡的效应物）的小鼠。注射功能获得性突变体PCSK 9（AAV 8-gof-PCSK 9）并喂食西方饮食16周的Mlkl−/−小鼠与注射AAV 8-gof-PCSK 9的wt对照组相比，显示出明显更少的斑块坏死、增加的纤维帽和改善的红细胞增多症。此外，高胆固醇血症Mlkl−/−小鼠在斑块和体外的促消退介质（包括Resolvin D1（RvD 1））显著增加，前列腺素类（包括血栓烷（TX））减少。我们发现NC释放的旺盛TX通过破坏巨噬细胞中的氧化磷酸化（OXPHOS）而损害凋亡细胞和NC的清除。此外，我们发现，NC不容易合成RvD 1和RvD 1的巨噬细胞的外源性管理拯救NC诱导的缺陷性红细胞增多症。RvD 1还通过激活p-AMPK、增加脂肪酸氧化和增强巨噬细胞中的OXPHOS来增强NC的摄取。这些结果表明，NC通过限制SPM（如RvD 1）的合成和通过在巨噬细胞的巨噬细胞库中的损伤来扰乱分辨率。此外，这些发现提供了RvD 1在巨噬细胞中指导促分解代谢程序的分子机制，并进一步表明RvD 1是限制组织中NC的潜在治疗策略。
Plaque necrosis is a key feature of defective resolution in atherosclerosis. Recent evidence suggests that necroptosis promotes plaque necrosis, therefore we sought to determine how necroptotic cells (NCs) impact resolution programs in plaques. To investigate the role(s) of necroptosis in advanced atherosclerosis, we used mice deficient of Mlkl, an effector of necroptosis. Mlkl−/− mice that were injected with a gain-of-function mutant PCSK9 (AAV8-gof-PCSK9) and fed a Western Diet for 16 weeks, showed significantly less plaque necrosis, increased fibrous caps and improved efferocytosis compared with AAV8-gof-PCSK9 injected wt controls. Additionally, hypercholesterolemic Mlkl−/− mice had a significant increase in pro-resolving mediators including Resolvin D1 (RvD1), and a decrease in prostanoids including thromboxane (TX) in plaques and in vitro. We found that exuberant TX released by NCs impaired the clearance of both apoptotic cells and NCs through disruption of oxidative phosphorylation (OXPHOS) in macrophages. Moreover, we found that NCs did not readily synthesize RvD1 and that exogenous administration of RvD1 to macrophages rescued NC-induced defective efferocytosis. RvD1 also enhanced the uptake of NCs via the activation of p-AMPK, increased fatty acid oxidation and enhanced OXPHOS in macrophages. These results suggest that NCs derange resolution by limiting SPM (e.g. RvD1) synthesis and through an impairment in the efferocytic repertoire of macrophages. Moreover, these findings provide a molecular mechanism for RvD1 in directing pro-resolving metabolic programs in macrophages and further suggests RvD1 as a potential therapeutic strategy to limit NCs in tissues.