Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia
Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia
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DOI：
10.1016/j.bbalip.2012.01.007
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发表时间：
2012-04-01
影响因子：
4.8
通讯作者：
Maysinger, Dusica
中科院分区：
文献类型：
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作者：
Khatchadourian, Armen;Bourque, Simon D.;Maysinger, Dusica
脂滴（LDs）是一种中性的富含脂质的细胞器，参与许多细胞过程。一个众所周知的例子是它们在被促炎刺激物（如源自革兰氏阴性细菌的脂多糖（LPS））激活后在白细胞中的积累。然而，LD和LD相关蛋白在大脑炎症过程中的作用尚不清楚。我们现在已经研究了它们在小胶质细胞中的动力学和调节，小胶质细胞是大脑中的常驻免疫细胞。我们发现LPS处理小胶质细胞导致LD在其中积聚，并且LD的大小增加。这种LD的诱导被甘油三酯生物合成的抑制剂三酸甘油酯C消除。LPS强烈激活c-Jun N-末端激酶（JNK）和p38 MAPK应激信号通路，并以时间依赖的方式增加LD相关蛋白perilipin-2（ADRP）的表达。免疫组化显示，围脂蛋白-2在LPS处理的小胶质细胞主要与LD共定位。p38 α/β（SB 203580）和PI 3 K/Akt通路（LY 294002）的抑制剂，但不是JNK（SP 600125）的抑制剂，减少LPS诱导的LD积累并消除LPS对围脂蛋白-2的激活作用。此外，胞质磷脂酶A（2）（cPLA（2）-α），花生四烯酸释放的关键酶，与LPS诱导的LD共定位。这些观察结果表明，LD可能在激活的小胶质细胞中的类花生酸合成中发挥重要作用：它们提供了一种新的见解来调节LD在大脑炎症细胞中的作用，并指出p38 α/β在LPS诱导的LD积累中的潜在作用。总的来说，我们的研究结果表明，LD形成和围脂蛋白-2诱导可能是中枢神经系统炎症的小胶质细胞生物标志物。(C)2012爱思唯尔有限公司版权所有。
Lipid droplets (LDs) are neutral lipid-rich organelles involved in many cellular processes. A well-known example is their accumulation in leukocytes upon activation by pro-inflammatory stimuli such as lipopolysaccharides (LPS) derived from gram-negative bacteria. A role of LDs and LD-associated proteins during inflammation in the brain is unknown, however. We have now studied their dynamics and regulation in microglia, the resident immune cells in the brain. We find that LPS treatment of microglia leads to the accumulation in them of LDs, and enhancement of the size of LDs. This induction of LDs was abolished by triacsin C, an inhibitor of triglyceride biosynthesis. LPS strongly activated c-Jun N-terminal kinase (JNK) and p38 MAPK stress signaling pathways and increased the expression of LD-associated protein perilipin-2 (ADRP) in a time-dependent manner. Immunostaining showed that perilipin-2 in LPS-treated microglia predominantly colocalized with LDs. Inhibitors of p38 alpha/beta (SB203580) and PI3K/Akt pathway (LY294002), but not that of JNK (SP600125), reduced LPS-induced LD accumulation and eliminated the activating effect of LPS on perilipin-2. In addition, cytosolic phospholipase A(2) (cPLA(2)-alpha), a key enzyme for arachidonic acid release, colocalized with LPS-induced LDs. These observations suggest that LDs may play an important role in eicosanoid synthesis in activated microglia: they provide a novel insight into the regulation of LDs in inflammatory cells of the brain and point to a potential role of p38 alpha/beta in LPS-induced LD accumulation. Collectively, our findings imply that LD formation and perilipin-2 induction could be microglial biomarkers of inflammation in the central nervous system. (C) 2012 Elsevier B.V. All rights reserved.