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PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia
iScience ( IF 4.6 ) Pub Date : 2020-09-16 , DOI: 10.1016/j.isci.2020.101570
Changyu Jiang , Zilong Wang , Christopher R. Donnelly , Kaiyuan Wang , Amanda S. Andriessen , Xueshu Tao , Megumi Matsuda , Junli Zhao , Ru-Rong Ji

The immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors.



中文翻译:

PD-1调节GABA能神经传递和GABA介导的镇痛和麻醉作用

免疫检查点抑制剂编程的细胞死亡蛋白1(PD-1)在免疫调节中起关键作用。最近的研究表明,在外周感觉神经元中有功能性PD-1表达,这有助于神经元兴奋性,疼痛和阿片类镇痛。在这里,我们报告PD-1在包括脊髓,丘脑和大脑皮层的中枢神经系统(CNS)中的神经元表达和功能。值得注意的是,在脊髓切片,脑切片和游离皮质神经元中,PD-1中和性免疫治疗药物Nivolumab抑制了GABA诱导的脊髓背角神经元,丘脑神经元和皮质神经元电流。在P d1 -/-中也观察到CNS神经元中GABA介导的电流减少。GABA受体表达无变化的小鼠。机械上,Nivolumab结合脊髓神经元并引发ERK磷酸化,从而抑制GABA电流。最后,Pd1缺乏会损害GABA介导的镇痛和麻醉作用。我们的发现揭示了PD-1作为中枢神经系统神经元抑制剂,可调节GABA能信号和GABA介导的行为。

更新日期:2020-10-02
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