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

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

doi:10.1172/jci.insight.137386

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.

Highlights

Cancer pain, reported by approximately 39.3%–66.4% of patients with cancer, severely reduces patients’ quality of life (1–3)
Cumulative evidence shows that tumors and surrounding tissue cells release various algogenic substances, including protons, proteases, endothelins, vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and transforming growth factor–β (TGF-β), in the tumor microenvironment to sensitize and injure primary sensory neurons (10, 14, 38–41)
A collaborative study from Ji’s and our laboratories demonstrated that cancers such as melanoma produce the antinociceptive mediator programmed death-ligand 1 (PD-L1) to suppress pain via its receptor, PD-1, expressed on dorsal root ganglion (DRG) neurons (15)

Summary

Introduction

Cancer pain, reported by approximately 39.3%–66.4% of patients with cancer, severely reduces patients’ quality of life (1–3). During tumor growth and invasion, multiple algogenic substances released from cancer cells, osteoblasts, osteoclasts, and nerve endings sensitize and activate primary afferent nociceptors in the cancer microenvironment (6, 7). TRPV1 is a ligand-gated nonselective cation channel, which is mainly expressed in small-diameter (43°C), extracellular protons, and vanilloid capsaicin (11). In a rat bone cancer model using Walker 256 mammary gland carcinoma cells, we observed that TRPV1 expression level and capsaicin-induced TRPV1 currents are increased in ipsilateral DRG neurons with tumor inoculation in bone, and blockade of TRPV1 reduces bone cancer pain (10). An earlier study from Ghilardi et al found that TRPV1-knockout mice show a significant reduction in ongoing and movement-evoked nocifensive behaviors in bone cancer mice (12)

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