Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus
Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus
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DOI：
10.1152/ajpheart.00247.2015
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发表时间：
2016-02-01
影响因子：
4.8
通讯作者：
Stern, Javier E.
中科院分区：
文献类型：
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作者：
Biancardi, Vinicia Campana;Stranahan, Alexis M.;Stern, Javier E.
ANG II被认为通过增加氧化应激和促进下丘脑室旁核（PVN）中的局部炎症来增加交感神经流出。然而，炎症和氧化应激对交感神经驱动的相对贡献仍然知之甚少，并且潜在的细胞和分子靶点还有待研究。ANG II已被证明可增强小胶质细胞上Toll样受体（TLR）4介导的信号传导。因此，在本研究中，我们旨在确定ANG II介导的小胶质细胞TLR 4信号的激活是否是PVN中启动局部氧化应激的关键分子靶点。我们在下丘脑小胶质细胞中发现了TLR 4和ANG Ⅱ 1型（AT（1））受体mRNA的表达，为这两种受体之间的潜在相互作用提供了分子证据。在下丘脑切片中，ANG II诱导PVN内的小胶质细胞活化（类似于65%的增加，P < 0.001），这种作用在功能性TLR 4缺失时减弱。如二氢乙锭荧光所示，在大鼠和小鼠的PVN内，ANG II增加了ROS的产生（两种情况下P < 0.0001），这种作用也依赖于功能性TLR 4的存在。小胶质细胞抑制剂米诺环素减弱了ANG II介导的ROS产生，但ANG II效应在PVN专一1-AT（1a）敲除小鼠中持续存在，支持非神经元来源（可能是小胶质细胞）对ANG II驱动的PVN ROS产生的贡献。总之，这些结果支持AT 1受体和TLR 4在介导ANG II依赖性小胶质细胞活化和PVN内氧化应激中的功能相互作用。更广泛地说，我们的研究结果支持中央肾素-血管紧张素系统和先天性免疫之间的功能相互作用，在调节神经体液流出PVN。
ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR) 4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT(1)) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (similar to 65% increase, P < 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P < 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT(1a) knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN.