PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia

Abstract

Summary 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 d1 −/− 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.

Morphine-3-glucuronide upregulates PD-L1 expression <i>via</i> TLR4 and promotes the immune escape of non-small cell lung cancer

“…These 2 observations also enhanced the clinical relevance and significance of our findings. Because the PD-1/PD-L1 axis has been recently reported to be involved in the modulation of acute and chronic pain including bone cancer pain 35 – 38 , it will be important to determine the possible effect of M3G-induced PD-L1 upregulation during the development of cancer pain. Whether the upregulation of PD-L1 caused by M3G increases the response of anti-PD-1 or anti-PD-L1 treatment should also be determined in future studies.…”

Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

“…PD1 is considered an inducible protein, and its expression is mainly limited to the thymus ( Ishida et al, 1992 ). Functional PD1 has also been found in the dorsal root ganglion ( Ishida et al, 1992 ) and other brain regions such as the thalamic and cortical neurons ( Jiang et al, 2020 ), suggesting a neuronal role in the brain. Although PD1/PDL1 blockade reportedly exerts strong anti-AD effects, the expression of PD1 and PDL1 in the brain of AD mouse model is still unclear.…”

Effects of combined chemotherapy and anti-programmed cell death protein 1 treatment on peripheral neuropathy and neuroinflammation in mice

“…21 Alternatively, microglia may become activated by increased neuronal activity mediated by PD-1 neutralisation as a recent study revealed that PD-1 is required for GABAergic signalling in the spinal cord dorsal horn and its deficiency causes an impaired analgesia. 18 In conclusion, our results demonstrate that both paclitaxel and anti-PD-1 treatments induce inhibition of neurite outgrowth and immune changes in the DRG and the spinal cord. However, anti-PD-1 does not increase the intensity of paclitaxel-induced pain hypersensitivity and "dying-back" axonal degeneration.…”

“…4,27 Blocking the PD-1 or PD-L1 pathway unmasks existing pain conditions, induces allodynia, 4,13,59 and suppresses GABAergic neurotransmission in spinal neurons. 18 PD-1 activation by PD-L1 reduces nociceptive neuron excitability 4 and suppresses bone cancer pain through inhibiting the function of transient receptor potential vanilloid 1 in DRG neurons 27 in mice. A recent systematic review and meta-analysis has shown that combining chemotherapy with anti-PD-1 treatment increased the incidence risk of peripheral neuropathy in patients with solid tumours.…”