PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1

Area of Science:

• Neuroscience
• Immunology
• Oncology

Background:

• Programmed cell death ligand-1 (PD-L1) typically suppresses T cell-mediated immunity.
• The function of PD-L1 and its receptor PD-1 in pain regulation and neuronal function remains largely unknown.

Purpose of the Study:

• To investigate the role of PD-L1 and PD-1 in modulating pain pathways and neuronal excitability.
• To explore the potential of targeting the PD-L1/PD-1 axis for pain management.

Main Methods:

• Utilized mouse models (including Pd1 knockout mice) and human dorsal root ganglion (DRG) neurons.
• Administered PD-L1, neutralized PD-L1, or blocked PD-1 in various pain assays.
• Assessed neuronal excitability, ion channel activity (SHP-1, TREK2 K+ channels), and pain behaviors (analgesia, allodynia, hypersensitivity).

Main Results:

• PD-L1, produced by both melanoma and neural tissues (DRG), demonstrated potent analgesic effects in naive mice via PD-1.
• PD-L1 neutralization or PD-1 blockade induced mechanical allodynia, while Pd1 knockout mice showed thermal and mechanical hypersensitivity.
• PD-L1 activation of PD-1 on nociceptive neurons inhibited excitability by activating SHP-1 and TREK2 K+ channels, suppressing sodium channels.
• Blocking PD-L1/PD-1 in melanoma-bearing mice led to spontaneous pain and allodynia.

Conclusions:

• PD-L1 acts as an endogenous inhibitor of acute and chronic pain.
• PD-L1/PD-1 signaling in DRG neurons is a critical regulator of nociception and neuronal excitability.
• These findings identify a novel role for PD-L1 as a neuromodulator and a potential therapeutic target for pain relief.