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

Nature Neuroscience volume 20, pages 917926 (2017) | Download Citation

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Abstract

Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 (Pdcd1) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K+ channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.

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Change history

  • 14 January 2019

    In the version of this article initially published, what was originally described as 'conditioned place preference' in a two-chamber mouse experiment could be better described as 'conditioned place avoidance'. The error occurred in several places. The error has not been corrected in the original article.

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Acknowledgements

This study is supported by NIH RO1 grants NS87988, DE17794 and DE22743 and National Science Fund of China (NSFC) 31420103903. Y.H.K. was supported by the National Research Foundation of Korea (NRF) 2013R1A6A3A04065858.

Author information

Author notes

    • Gang Chen
    •  & Yong Ho Kim

    These authors contributed equally to this work.

Affiliations

  1. Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.

    • Gang Chen
    • , Yong Ho Kim
    • , Hao Luo
    • , Da-Lu Liu
    • , Zhi-Jun Zhang
    • , Mark Lay
    • , Wonseok Chang
    •  & Ru-Rong Ji
  2. Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.

    • Gang Chen
  3. Department of Physiology, College of Medicine, Gachon University, Incheon, Republic of Korea.

    • Yong Ho Kim
  4. Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.

    • Hui Li
    • , Hao Luo
    • , Yu-Qiu Zhang
    •  & Ru-Rong Ji
  5. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.

    • Ru-Rong Ji

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Contributions

G.C. developed the project, performed behavioral and histochemical experiments and prepared the final figures. Y.H.K. conducted electrophysiology in mouse and human DRG neurons. H. Li and H. Luo performed spinal cord recordings and behavioral test in bonce caner model under the guidance of Y.-Q.Z. D.-L.L. performed recordings in whole-mount mouse DRGs. Z.-J.Z. contributed to histochemistry in Pd1 knockout mice. M.L. did some in situ hybridization experiment. W.C. conducted some electrophysiology in mouse DRG neurons. R.-R.J. and Y.-Q.Z. supervised the project. R.-R.J., G.C. and Y.-Q.Z. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yu-Qiu Zhang or Ru-Rong Ji.

Integrated supplementary information

Supplementary figures

  1. 1.

    PD-L1 secretion in melanoma cells and Pdl1 miRNA expression in mouse DRG neurons

  2. 2.

    Spontaneous pain and mechanical sensitivity in naive mice and nivolumab binding in mouse DRG neurons and sciatic nerve

  3. 3.

    PD-L1 or anti-PD-1 treatment fails to change mechanical sensitivity in Pd1−/− mice

  4. 4.

    Pd1−/− mice display normal central innervations in the spinal cord dorsal horn

  5. 5.

    Pd1−/− mice display normal distribution patterns of C-fiber and A-fiber neurons and have no neuronal loss in DRGs

  6. 6.

    Spinal application of PD-L1 suppresses excitatory synaptic transmission in lamina IIo neurons in spinal cord slices and inhibits neuropathic pain and baseline pain in mice

  7. 7.

    Spinal application of PD-L1 inhibits mechanical hypersensitivity and firing of spinal WDR neurons in a model of bone cancer in rats.

  8. 8.

    PD-L1 induces phosphorylation of SHP1 in mouse DRG neurons

  9. 9.

    TREK2 activation by PD-L1 in CHO cells and schematic illustration of PD-L1-induced silencing of nociceptive neurons

  10. 10.

    PD-1 immunofluorescence in DRG neurons and nerve axons of human tissue sections

  11. 11.

    Intraplantar (i.pl.) injection of soluble PD-1 (sPD-1) evokes spontaneous pain and mechanical allodynia in melanoma mice

  12. 12.

    Intraplantar (i.pl.) injection of soluble PD-1 (sPD1) does not change immune responses in melanoma-bearing hindpaw skin in the acute phase

  13. 13.

    Pd1-targeting siRNA decreases PD-1 expression in DRG and sciatic nerve but not spinal cord dorsal horn tissues

  14. 14.

    Induction of mechanical allodynia and spontaneous pain by systemic or local injection of anti-PD-1 antibodies and SHP-1 inhibitor in melanoma mice

  15. 15.

    Numbers of animals (mice and rats) used in this study

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15

  2. 2.

    Supplementary Methods Checklist

Videos

  1. 1.

    Spontaneous pain in top left mouse

    Video 1 (40 s) shows spontaneous pain in top left mouse. The bottom two control mice received vehicle injection and did not show spontaneous pain, despite massive growth of melanoma in a hindpaw.

  2. 2.

    Spontaneous pain in top right mouse

    Video 2 (40 s) shows spontaneous pain in top right mouse. The bottom two control mice received vehicle injection and did not show spontaneous pain, despite massive growth of melanoma in a hindpaw.

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DOI

https://doi.org/10.1038/nn.4571

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