2. Academic Validation
  3. PD-1 Attenuates Neuropathic Pain by Ameliorating NLRP3 Inflammasome-Mediated Microglia Pyroptosis

PD-1 Attenuates Neuropathic Pain by Ameliorating NLRP3 Inflammasome-Mediated Microglia Pyroptosis

  • Mol Neurobiol. 2025 Jul 19. doi: 10.1007/s12035-025-05225-5.
Daling Deng 1 2 3,  Lulin Ma 1 2 3,  Jiwei Shen 1 2 3,  Li Huang 1 2 3,  Tianhao Zhang 1 2 3,  Xinxin Yang 1 2 3,  Shiqian Huang 1 2 3,  Wenjing Zhao 1 2 3,  Yuxi Zhou 1 2 3,  Shiwen Fan 1 2 3,  Kaixin Wang 1 2 3,  Xiangdong Chen 4 5 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
  • 2 Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3 Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 4 Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China. xdchen@hust.edu.cn.
  • 5 Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. xdchen@hust.edu.cn.
  • 6 Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430022, China. xdchen@hust.edu.cn.
PMID: 40682720 DOI: 10.1007/s12035-025-05225-5
Abstract

Neuropathic pain lacks effective clinical treatments due to its complex pathogenesis. Growing evidence indicates that programmed cell death receptor-1 (PD-1) plays a vital role in reducing neuropathic pain. Recent studies have also implicated the nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing 3 (NLRP3 inflammasome and its associated Pyroptosis in the pathophysiology of various pain types. However, it remains unclear whether PD-1 relieves neuropathic pain by regulating NLRP3 inflammasome activation and subsequent Pyroptosis. This study found the dynamics of spinal cord PD-1 expression in a spared nerve injury (SNI) model of neuropathic pain. Additionally, SNI markedly increased the activation of the NF-κB pathway, NLRP3 inflammasomes, and Pyroptosis in the spinal cord. Intrathecal administration of the PD-1 inhibitor RMP1-14 worsened SNI-induced neuropathic pain and significantly heightened the inflammatory response, NF-κB pathway activation, and NLRP3 inflammasome assembly. Notably, RMP1-14 specifically promoted microglial Pyroptosis, with no significant effect on neuronal Pyroptosis. Conversely, intrathecal injection of the NLRP3 Inhibitor MCC950 alleviated pain hypersensitivity and reduced inflammation. These findings suggest that the analgesic effects of PD-1 are linked to suppression of the NLRP3 inflammasome and its regulation of microglial Pyroptosis, highlighting PD-1 as a potential therapeutic target for neuropathic pain.

Keywords

Inflammation; NLRP3; Neuropathic pain; PD-1.

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