Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Immunity. 2022 Aug 9;55(8):1466-1482.e9. doi: 10.1016/j.immuni.2022.06.018. Epub 2022 Jul 20.
Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFB-Kv4.3 pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.
尽管许多研究已经探讨了影响神经元活动的调节回路，但局部非突触机制仍不清楚，这些机制决定了神经元的兴奋性。在这里，我们发现小胶质细胞在稳态下防止下丘脑室旁核（PVN）中的前交感神经元过度激活。小胶质细胞持续释放血小板衍生生长因子（PDGF）B，通过神经元细胞上的 PDGFRα 信号传递，并促进其关键亚基 Kv4.3 的表达，Kv4.3 是传导钾电流的关键亚基。小胶质细胞消融、小胶质细胞 PDGFB 的条件性缺失或 PVN 中神经元 PDGFRα 表达的抑制，都会增加前交感神经元和交感神经输出的兴奋性，导致严重的自主神经功能障碍。PDGFB-Kv4.3 通路的破坏使小鼠易患高血压，而中枢外源性 PDGFB 的补充在小鼠受到高血压损伤时抑制升压反应。我们的研究结果表明，驻留小胶质细胞在维持交感神经输出平衡方面具有非免疫作用，这对于预防心血管疾病非常重要。
