Isovitexin-Mediated Regulation of Microglial Polarization in Lipopolysaccharide-Induced Neuroinflammation via Activation of the CaMKKβ/AMPK-PGC-1α Signaling Axis
Isovitexin-Mediated Regulation of Microglial Polarization in Lipopolysaccharide-Induced Neuroinflammation via Activation of the CaMKKβ/AMPK-PGC-1α Signaling Axis
复制标题
Isovitexin 通过激活 CaMKKβ/AMPK-PGC-1α 信号轴介导脂多糖诱导的神经炎症中小胶质细胞极化的调节
DOI：
10.3389/fimmu.2019.02650
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发表时间：
2019-11-14
影响因子：
7.3
通讯作者：
Liu, Dianfeng
中科院分区：
文献类型：
--
作者：
Liu, Bingrun;Huang, Bingxu;Liu, Dianfeng
小胶质细胞是大脑的免疫细胞，在中枢神经系统的微环境调节中发挥重要作用。活化的小胶质细胞能够获得促炎（M1）表型和抗炎（M2）表型。小胶质细胞的过度激活是神经毒性的，并可能导致神经炎性脑疾病。脑内的神经炎症在许多精神和神经疾病的病理生理学中起着至关重要的作用。抑制M1小胶质细胞和促进M2小胶质细胞被证明可以通过减少神经炎症来治疗和预防这些疾病。异牡荆素（IVX）具有抗炎特性，并通过血脑屏障;然而，调节IVX介导的小胶质细胞极化的分子机制仍不清楚。在BV-2细胞和小鼠原代小胶质细胞中，IVX抑制了M1小胶质细胞标志物的表达，增强了M2小胶质细胞标志物的表达，并增强了白细胞介素10（IL-10）的释放。IVX促进LPS诱导的小胶质细胞活化过程中过氧化物酶体增殖物激活受体γ（PPARγ）和PPARγ共激活因子1α（PGC-1α）的表达。抑制PPARγ和PGC-1α可减弱IVX对LPS诱导的小胶质细胞极化的调节作用。IVX可增加BV-2细胞中p-CaMKKβ、p-AMPK和PGC-1α的表达。在LPS处理的细胞中，用STO-609抑制CaMKK β或用CaMKKβ siRNA敲低CaMKKβ可减弱IVX介导的M2小胶质细胞极化。在LPS处理的小鼠中，CaMKKβ和PGC-1α的抑制减弱了IVX介导的预防疾病行为和增强IVX介导的M2小胶质细胞极化。IVX通过激活CaMKKβ/AMPK-PGC-1α信号轴，促进M2小胶质细胞极化，从而发挥抗炎作用。
Microglia are the brain's immune cells and play an important role in regulating the microenvironment in the central nervous system. Activated microglia are capable of acquiring the pro-inflammatory (M1) phenotype and anti-inflammatory (M2) phenotype. Overactivation of microglia is neurotoxic and may lead to neuroinflammatory brain disorders. Neuroinflammation in the brain plays a crucial role part in the pathophysiology of many psychiatric and neurological diseases. The inhibition of M1 microglia and promotion of M2 microglia was demonstrated to treat and prevent these diseases through reduced neuroinflammation. Isovitexin (IVX) has anti-inflammatory properties and passes through the blood-brain barrier; however, the molecular mechanism that modulates IVX-mediated microglial polarization remains unclear. In BV-2 cells and mouse primary microglia, IVX suppressed the expression of M1 microglial markers, enhanced the expression of M2 microglial markers, and enhanced the release of interleukin 10 (IL-10). IVX promoted the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) in LPS-induced microglial activation. The inhibition of PPARγ and PGC-1α attenuated the regulatory effect of IVX in LPS-induced microglial polarization. IVX increased the expression of p-CaMKKβ, p-AMPK, and PGC-1α in BV-2 cells. Inhibition of CaMKKβ with STO-609 or knockdown of CaMKKβ with CaMKKβ siRNA attenuated IVX-mediated M2 microglial polarization in LPS-treated cells. In LPS-treated mice, the inhibition of CaMKKβ and PGC-1α attenuated the IVX-mediated prevention of sickness behavior and enhanction of IVX-mediated M2 microglial polarization. IVX promoted M2 microglial polarization which exerted anti-inflammatory effects on LPS-induced neuroinflammation via the activation of the CaMKKβ/AMPK-PGC-1α signaling axis.