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Electroacupuncture Alleviates CFA-Induced Inflammatory Pain via PD-L1/PD-1-SHP-1 Pathway

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Abstract

Inflammatory pain is difficult to treat clinically, but electroacupuncture (EA) has been demonstrated to be effective in alleviating inflammatory pain. Programmed cell death ligand-1 (PD-L1) and its downstream signal, Src homology region two domain-containing phosphatase-1 (SHP-1) have a critical role in relieving inflammatory pain. However, whether the PD-L1/PD-1-SHP-1 pathway mediates the analgesic and anti-inflammatory effects of EA in inflammatory pain remains unclear. Here, we observed that EA reversed the complete Freund’s adjuvant (CFA)-induced hyperalgesia. EA reduced the expression of IL-6, iNOS, and NF-κB pathway in dorsal root ganglia (DRG) on day 7 after CFA injection but had no effect on the expression of IL-6, iNOS, and NF-κB PP65 on day 21 after CFA injection. Moreover, EA upregulated the protein levels of the PD-L1/PD-1-SHP-1 pathway on day 7 and day 21 after CFA injection. Furthermore, EA upregulated PD-L1 expression in calcitonin gene-related peptide (CGRP)+ but not in isohaemagglutinin B4 (IB4)+ and NF200+ neurons on day 7 and day 21 after CFA injection. Intrathecal injection of the PD-L1/PD-1 inhibitor BMS-1 (50 or 100 µg) blocked the EA-induced analgesic effect, significantly increased IL-6 and iNOS levels, and reduced the levels of PD-L1/PD-1-SHP-1. BMS-1 (50 or 100 µg) significantly reduced the expression of PD-L1 in IB4+, CGRP+, and NF200+ neurons. Our results show that EA’s anti-inflammatory and analgesic effects are associated with activating the PD-L1/PD-1-SHP-1 pathway and suppressing its regulated neuroinflammation. This study provides a new potential therapeutic target for treating inflammatory pain.

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Data Availability

All the data supporting the findings of this study are available within the article and from the corresponding author upon reasonable request.

Abbreviations

EA:

Electroacupuncture

PD-L1:

Programmed death ligand-1

PD-1:

Programmed cell death receptor

SHP-1:

Src homology region two domain-containing phosphatase-1

DRG:

Dorsal root ganglia

Sting:

Stimulator of interferon

NGF:

Nerve growth factor

IL-2:

Interleukin-2

IFN-γ:

Interferon-γ

PWT:

Paw withdraw threshold

PWL:

Paw withdraw latency

CGRP:

Calcitonin gene-related peptide

IB4:

IsohemagglutininB4

NF-κB:

Nuclear transcription factor kappa B

TNF-α:

Tumour necrosis factor-α

PBS:

Phosphate buffer saline

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

5-HT (serotonin):

5-Hydroxytryptamine

iNOS:

Inducible nitric oxide synthase

NSAIDs:

Nonsteroidal anti-inflammatory drugs

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Funding

This work was supported by the National Key Research and Development Program of China (grant 2018YFC2001802 to X. Chen); the National Natural Science Foundation (grant 82071251 to X. Chen); the Hubei Province Key Research and Development Program (grant 2021BCA145 to X. Chen).

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  1. Daling Deng and Feng Xu equally contributed to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Daling Deng, Feng Xu, Lulin Ma, Tianhao Zhang, Yafeng Wang, Shiqian Huang, Wenjing Zhao & Xiangdong Chen

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  1. Daling Deng
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Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Daling Deng and Feng Xu. The first draft of the manuscript was written by Daling Deng, and all authors commented on previous versions of the manuscript. Daling Deng and Feng Xu contribute equally to this work. All authors read and approved the final manuscript.

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Correspondence to Xiangdong Chen.

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All experimental procedures were carried out in accordance with the ethical guidelines of the International Association for the Study of Pain (Zimmermann 1983) and approved by the Animal Care Committee at Huazhong University of Science and Technology.

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Deng, D., Xu, F., Ma, L. et al. Electroacupuncture Alleviates CFA-Induced Inflammatory Pain via PD-L1/PD-1-SHP-1 Pathway. Mol Neurobiol 60, 2922–2936 (2023). https://doi.org/10.1007/s12035-023-03233-x

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