Jiang Changyu, Wang Zilong, Donnelly Christopher R, Wang Kaiyuan, Andriessen Amanda S, Tao Xueshu, Matsuda Megumi, Zhao Junli, Ji Ru-Rong
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
iScience. 2020 Sep 16;23(10):101570. doi: 10.1016/j.isci.2020.101570. eCollection 2020 Oct 23.
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 P 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.
免疫检查点抑制剂程序性细胞死亡蛋白1（PD-1）在免疫调节中起关键作用。最近的研究表明，外周感觉神经元中存在功能性PD-1表达，这与神经元兴奋性、疼痛和阿片类镇痛有关。在此，我们报告了PD-1在中枢神经系统（CNS）中的神经元表达及功能，包括脊髓、丘脑和大脑皮层。值得注意的是，在脊髓切片、脑切片和离体皮层神经元中，PD-1中和性免疫治疗药物纳武单抗可抑制脊髓背角神经元、丘脑神经元和皮层神经元中γ-氨基丁酸（GABA）诱导的电流。在P 小鼠中也观察到中枢神经系统神经元中GABA介导的电流减少，而GABA受体表达无变化。从机制上讲，纳武单抗与脊髓神经元结合并引发细胞外信号调节激酶（ERK）磷酸化，从而抑制GABA电流。最后，Pd1缺陷会损害GABA介导的镇痛和麻醉作用。我们的研究结果揭示了PD-1作为一种中枢神经系统神经元抑制剂，可调节GABA能信号传导和GABA介导的行为。
