Resistin inhibits neuronal autophagy through Toll-like receptor 4
Resistin inhibits neuronal autophagy through Toll-like receptor 4
复制标题
抵抗素通过Toll样受体4抑制神经元自噬
DOI：
10.1530/joe-18-0096
复制
发表时间：
2018-07-01
影响因子：
4
通讯作者：
Taouis, Mohammed
中科院分区：
文献类型：
--
作者：
Miao, Jie;Benomar, Yacir;Taouis, Mohammed
自噬是在能量剥夺细胞和非饥饿细胞中诱导的非选择性降解途径，其主要通过消除构成活性氧的重要来源的损伤和老化的线粒体参与细胞炎症反应。我们以前曾报道过，在神经细胞中，JNK/TLR 4信号通路诱导炎症和胰岛素抵抗。然而，抵抗素诱导的炎症对神经元自噬的影响尚不清楚。在本研究中，我们假设抵抗素诱导的神经炎症至少部分归因于神经细胞自噬通路的损伤。我们的数据显示，在SH-SY 5 Y人神经母细胞瘤细胞系中，如通过抑制主要自噬标记物所证明的那样，Doprin减少神经元自噬。此外，TLR 4的沉默完全消除了这些作用。抵抗素还抑制AMPK磷酸化，并增加Akt/mTOR的磷酸化，与活化的自噬形成对比，其中AMPK磷酸化增强而mTOR抑制。在体内，Gluron治疗抑制WT小鼠下丘脑中自噬标志物的mRNA表达，但在Tlr 4-/-小鼠中不抑制。此外，在WT小鼠的弓状核中，LC 3（自噬的标志物）标记强烈减弱，并且这种作用在Tlr 4-/-小鼠中被消除。综上所述，我们的研究结果清楚地揭示了Tumann/TLR 4作为神经元自噬的一种新的调节途径。
Autophagy is a non-selective degradation pathway induced in energy-deprived cells and in non-starved cells by participating in cellular inflammatory responses mainly through the elimination of injured and aged mitochondria that constitute an important source of reactive oxygen species. We have previously reported that resistin/TLR4 signaling pathway induces inflammation and insulin resistance in neuronal cell. However, the impact of resistin-induced inflammation on neuronal autophagy is unknown. In the present study, we hypothesized that resistin-induced neuroinflammation could be attributed, at least partially, to the impairment of autophagy pathways in neuronal cells. Our data show that resistin decreases neuronal autophagy as evidenced by the repression of the main autophagy markers in SH-SY5Y human neuroblastoma cell line. Furthermore, the silencing of TLR4 completely abolished these effects. Resistin also inhibits AMPK phosphorylation and increases that of Akt/mTOR contrasting with activated autophagy where AMPK phosphorylation is augmented and mTOR inhibited. In vivo, resistin treatment inhibits the mRNA expression of autophagy markers in the hypothalamus of WT mice but not in Tlr4-/- mice. In addition, resistin strongly diminished LC3 (a marker of autophagy) labeling in the arcuate nucleus of WT mice, and this effect is abolished in Tlr4-/- mice. Taken together, our findings clearly reveal resistin/TLR4 as a new regulatory pathway of neuronal autophagy.