PD-L1 and PD-1 expressed in trigeminal ganglia may inhibit pain in an acute migraine model

Shi, Shengjun; Han, Yuhang; Wang, Dan; Guo, Ping; Wang, Jiali; Ren, Tongli; Wang, Wuqing

doi:10.1177/0333102419883374

Cited by 15 publications

(4 citation statements)

References 33 publications

(35 reference statements)

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“…Three issues should be addressed. First, although our results and recent studies showed that PD-1 (encoded by Pdcd1) mRNA and protein were expressed in primary sensory neurons and were involved in acute and chronic pain as well as opioid-induced hyperalgesia ( 15 , 43 , 46 ), single-cell RNA-Seq failed to detect Pdcd1 mRNA expression ( 47 – 50 ) in the DRG neurons. A possible explanation is that single-cell RNA-Seq can only detect a limited transcriptome; some low- to medium-expressed but important genes in sensory neurons might be missed.…”

Section: Discussioncontrasting

confidence: 80%

“…A collaborative study from Ji’s and our laboratories demonstrated that cancers such as melanoma produce the antinociceptive mediator PD-L1 to suppress pain via its receptor, PD-1, expressed on DRG neurons ( 15 ). PD-1/PD-L1 signaling in the trigeminal ganglia was also reported to be involved in acute nitroglycerin-induced hyperalgesia ( 43 ). In the present study we further provided several lines of evidence to support the analgesic effect of PD-L1 in LLC cell–induced mouse bone cancer pain.…”

Section: Discussionmentioning

confidence: 99%

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

Liu¹,

Cao²,

Zhao³

et al. 2020

JCI Insight

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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 Na V 1.8 + 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.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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

Liu¹,

Cao²,

Zhao³

et al. 2020

JCI Insight

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“…Briefly, slices were incubated with anti-tryptase antibody (1:100, Santa, USA) and anti-EGF antibody (1:700, Santa, USA) at 4°C overnight, and then incubated with the secondary antibody at room temperature for 2h. 40 Immunofluorescence samples were observed and photographed with an inverted microscope (Leica, Germany). Image J software (NIH, USA) was used to analyze the mean fluorescence intensity.…”

Section: Methodsmentioning

confidence: 99%

EGF Protects Epithelial Cells from Barrier Damage in Chronic Rhinosinusitis with Nasal Polyps

Chen¹,

Liu²,

Liu³

et al. 2022

JIR

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Background The aim of this study is to investigate the potential key genes related to Chronic rhinosinusitis with nasal polyps (CRSwNP). Methods Datasets GSE36830 and GSE72713 were obtained from Gene Expression Omnibus. Dataset GSE36830 was used to identify differentially expressed genes in CRSwNP patients. GO, KEGG analysis, and PPI network analysis were applied to further investigate the function of DEGs in CRSwNP. GSEA was also performed to explore the mechanisms of DEGs. Dataset GSE72713 was applied to validate the key gene. Moreover, to detect the expression of target gene, nasal polyp tissues and middle turbinate specimens were collected from CRSwNP patients (n = 20) and controls (n = 20), respectively. RT-PCR, Western blot, and immunofluorescence staining were applied. HE and AB-PAS staining were used to assess the infiltration of inflammatory cells. The proliferation and migration ability of human nasal epithelial cells (HNEpCs) were tested via Cell Counting kit-8, wound healing assay and Transwell migration assay. Air–liquid interface was used to culture primary human nasal epithelial cells (pHNECs) from health controls and nasal polyp tissues of CRSwNP patients. Results A total of 1035 DEGs were identified, and 661 genes were up-regulated and 374 genes were down-regulated. According to PPI network analysis, the top 10 scored genes were identified. Among them, only EGF was down-regulated in CRSwNP. Meanwhile, GSEA result shows that EGF is significantly enriched in WNT activated receptor activity. CCK-8, wound healing assay, and transwell migration assay indicated that recombinant human EGF can promote the proliferation and migration of HNEpCs in vitro. Immunofluorescence staining shows that rhEGF can increase the expression of ZO-1 in pHNECs from nasal polyp tissues. Conclusion Bioinformatics analysis and in vitro experiments were used to explore the pathogenesis of CRSwNP, and the results showed that EGF may play an important role in the protection of nasal epithelial barrier.

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“…Recent studies have demonstrated that the immune checkpoints PD-1 and PD-L1 are expressed in the nervous system, including the trigeminal ganglion, 46 spinal dorsal horn, thalamic, and cortical neurons. 18 Furthermore, the expression of PD-1 on both sciatic nerve axons and the dorsal root ganglion (DRG) neurons suggests that it undergoes axonal transport from DRG cell bodies to peripheral axons.…”

Section: Introductionmentioning

confidence: 99%

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

Livni

Keating

Fiore

et al. 2021

PAIN

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A modern approach for cancer treatment is the use of immunotherapy, and particularly immune checkpoint inhibitors, such as antiprogrammed cell death protein 1 (PD-1), alone and in combination with chemotherapy. The PD-1 pathway plays a crucial role in inhibiting immune responses and recently has been shown to modulate neuronal activity. However, the impact of PD-1 blockade on the development of chemotherapy-induced peripheral neuropathy is currently unknown. In this study, we show that C57BL/6 mice treated with the chemotherapeutic drug paclitaxel or cotherapy (paclitaxel and anti-PD-1), but not with anti-PD-1 alone, exhibited increased mechanical sensitivity of the hind paw. Both chemotherapy and immunotherapy caused a reduction in neurite outgrowth of dorsal root ganglion (DRG) explants derived from treated mice, whereas only paclitaxel reduced the neurite outgrowth after direct in vitro treatment. Mice treated with anti-PD-1 or cotherapy exhibited distinct T-cell changes in the lymph nodes and increased T-cell infiltration into the DRG. Mice treated with paclitaxel or cotherapy had increased macrophage presence in the DRG, and all treated groups presented an altered expression of microglia markers in the dorsal horn of the spinal cord. We conclude that combining anti-PD-1 immunotherapy with paclitaxel does not increase the severity of paclitaxel-induced peripheral neuropathy. However, because anti-PD-1 treatment caused significant changes in DRG and spinal cord immunity, caution is warranted when considering immune checkpoint inhibitors therapy in patients with a high risk of developing neuropathy.

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PD-L1 and PD-1 expressed in trigeminal ganglia may inhibit pain in an acute migraine model

Cited by 15 publications

References 33 publications

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

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

EGF Protects Epithelial Cells from Barrier Damage in Chronic Rhinosinusitis with Nasal Polyps

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

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