Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia
Ben-Long Liu, Qi-Lai Cao, Xin Zhao, Hui-Zhu Liu, Yu-Qiu Zhang
Ben-Long Liu, Qi-Lai Cao, Xin Zhao, Hui-Zhu Liu, Yu-Qiu Zhang
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Research Article Neuroscience

Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia

Abstract

Recently programmed death-ligand 1 (PD-L1) receptor PD-1 was found in dorsal root ganglion (DRG) neurons, and PD-L1 activates PD-1 to inhibit inflammatory and neuropathic pain by modulating neuronal excitability. However, the downstream signaling of PD-1 in sensory neurons remains unclear. Here, we show that PD-L1 activated Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) to downregulate transient receptor potential vanilloid 1 (TRPV1) in DRG neurons and inhibit bone cancer pain in mice. Local injection of PD-L1 produced analgesia. PD-1 in DRG neurons colocalized with TRPV1 and SHP-1. PD-L1 induced the phosphorylation of SHP-1 in DRG TRPV1 neurons and inhibited TRPV1 currents. Loss of TRPV1 in mice abolished bone cancer–induced thermal hyperalgesia and PD-L1 analgesia. Conditioned deletion of SHP-1 in NaV1.8+ neurons aggravated bone cancer pain and diminished the inhibition of PD-L1 on TRPV1 currents and pain. Together, our findings suggest that PD-L1/PD-1 signaling suppresses bone cancer pain via inhibition of TRPV1 activity. Our results also suggest that SHP-1 in sensory neurons is an endogenous pain inhibitor and delays the development of bone cancer pain via suppressing TRPV1 function.

Authors

Ben-Long Liu, Qi-Lai Cao, Xin Zhao, Hui-Zhu Liu, Yu-Qiu Zhang

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Figure 2

Involvement of PD-L1/PD-1 in mouse bone cancer pain.

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Involvement of PD-L1/PD-1 in mouse bone cancer pain. (A–D) Local (A and ...
(A–D) Local (A and B) and lumbar puncture (LP) injection (C and D) of PD-L1 alleviates bone cancer–induced thermal hyperalgesia (A and C) and mechanical allodynia (B and D) on PTD 21. *P < 0.05, **P < 0.01 versus vehicle control; 2-way RM ANOVA followed by post hoc Student-Newman-Keuls test; n = 8 vehicle, 7 PD-L1 2 μg, 8 PD-L1 5 μg for A and B, n = 8 vehicle and 7 PD-L1 10 ng for C and D (mice). (E–G) Local injection of PD-L1 ameliorates bone cancer–induced changes in swing (E), stand (F), and print area (G) on PTD 21 by CatWalk gait analysis. *P < 0.05, **P < 0.01 versus vehicle control; 2-way RM ANOVA followed by post hoc Student-Newman-Keuls test; n = 8 vehicle and 9 PD-L1 2 μg (mice). (H) Schematic of the protocol for conditioned place preference (CPP). (I) Local injection of PD-L1 induces CPP. *P < 0.05 versus preconditioning; 2-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 6 vehicle and 6 PD-L1 (mice). (J) Western blot analysis reveals an increase in the level of PD-L1 in the affected bone after tumor inoculation. PD-L1 level is expressed as fold increase compared with sham controls at each corresponding time point. **P < 0.01 versus sham control, 1-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 6 sham mice, 4 PTD 7 mice, 4 PTD 14 mice, 6 PTD 21 mice. (K and L) Neutralization of PD-1 by nivolumab (anti–PD-1 antibody, 10 mg/kg, i.v.) induces thermal hyperalgesia (K) and mechanical allodynia (L) in the early phase of bone cancer (PTD 7). *P < 0.05, **P < 0.01 versus IgG control; 2-way RM ANOVA followed by post hoc Student-Newman-Keuls test; n = 8 human IgG4 and 8 nivolumab (mice).