Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae.
Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae.
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DOI：
10.1161/atvbaha.114.303342
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Razani B
中科院分区：
文献类型：
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作者：
Emanuel R;Sergin I;Bhattacharya S;Turner J;Epelman S;Settembre C;Diwan A;Ballabio A;Razani B
最近关于巨噬细胞特异性自噬缺陷小鼠致动脉粥样硬化表型的报道重新引起了人们对自噬-溶酶体系统在动脉粥样硬化中作用的兴趣。溶酶体具有处理外源物质（包括脂质）和自噬衍生的货物（如功能障碍的蛋白质/细胞器）的独特能力。我们的目的是了解致动脉粥样硬化的脂质环境对巨噬细胞溶酶体的影响，并评估调节该系统的新方法。利用各种互补技术，我们表明，氧化的低密度脂蛋白和胆固醇晶体，动脉粥样硬化中常见的脂质种类，导致培养的巨噬细胞中的溶酶体功能障碍。很容易观察到溶酶体pH、蛋白水解能力、膜完整性和形态的破坏。使用流式细胞术，我们发现从动脉粥样硬化斑块分离的巨噬细胞也显示溶酶体功能障碍的特征。然后，我们研究了增强溶酶体功能是否有益。TFEB是唯一已知的作为溶酶体生物发生的主要调节因子的转录因子，尽管其在巨噬细胞中的作用尚未被研究。氯喹或致动脉粥样硬化脂质诱导的溶酶体应激导致TFEB核转位以及溶酶体和自噬基因的激活。TFEB在巨噬细胞中的过表达进一步增强了这种促降解反应，并挽救了致动脉粥样硬化脂质负荷的几种有害作用，如通过钝化的溶酶体功能障碍、促炎细胞因子IL-1β分泌减少、胆固醇流出增加和多聚泛素化蛋白聚集减少所证明的。总之，这些数据表明，溶酶体功能显着受损动脉粥样硬化，并表明诱导巨噬细胞中的溶酶体生物合成程序具有抗动脉粥样硬化的作用。
Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and evaluate novel ways to modulate this system. Utilizing a variety of complementary techniques, we show that oxidized LDL and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. Disruptions in lysosomal pH, proteolytic capacity, membrane integrity, and morphology are readily seen. Using flow cytometry, we find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. TFEB is the only known transcription factor that is a master regulator of lysosomal biogenesis, although its role in macrophages has not been studied. Lysosomal stress induced by chloroquine or atherogenic lipids leads to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading as evidenced by blunted lysosomal dysfunction, reduced secretion of the proinflammatory cytokine IL-1β, enhanced cholesterol efflux, and decreased polyubiquitinated protein aggregation. Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has anti-atherogenic effects.