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Electroacupuncture alleviates neuropathic pain caused by SNL by promoting M2 microglia polarization through PD-L1
Qiaoyun Wu1, Yujun Zheng1, Jiaying Yu1
1Department of Physical Medicine and Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Integrative & Optimized Medicine Research Center, China-USA Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; The Wenzhou Key Laboratory for Rehabilitation Research, The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, China.
Abstract:
As a common clinical disease, neuropathic pain is difficult to be cured with drugs. The occurrence and progression of pain is closely related to the response of spinal microglia. Aspartof the regulation of microglialactivity,PD-L1 playsacriticalrole. Loss of PD-L1 promoted the polarization of M1-like microglia. Increased expression of PD-L1 promoted M2-like polarization. Electroacupuncture has a significant analgesic effect in clinical practice, but its specific mechanism remains to be further explored. In this study, we verified the role of PD-L1 in EA analgesia and the underlying molecular mechanism through spinal nerve ligation (SNL) in rats and lipopolysaccharide (LPS)-treated BV2 microglial cells. Forbehavioralstudiesofrats,mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured, and spinal cord neuros were examined under transmission electron microscopyto determine changes to their myelin structure. The expression levels of PD-L1 and M1/M2-specific markers in rat spinal cord and BV2 microglial cells were measured by enzyme-linked immunosorbent assay, flow cytometry, immunofluorescence staining and Western blot analysis. Our study showed that EA increased the pain threshold, reduced the destruction of myelin structure, promoted the expression of PD-L1 and PD-1, inhibited the MAPK signaling pathway, and promoted the conversion of microglial polarization from the M1 phenotype to the M2 phenotype in SNL rats. PD-L1 knockdown reversed these effects of EA. In addition, PD-L1 knockdown activated the MAPK signaling pathway, promoted microglial polarization to the M1 phenotype, decreased the expression of anti-inflammatory mediators and increased the expression of proinflammatory factors in LPS-stimulated BV2 microglial cells. Our results showed that EA may regulate the excitability of primary afferent neurons through PD-L1 and then inhibit the MAPK signaling pathway to promote the transformation of activated M1 microglia into M2 microglia, reduce inflammatory reactions, and finally achieve analgesic effects. A therapy targeting PD-L1 may be an effective strategy for treating neuropathic pain.
Insights
Electroacupuncture (EA) alleviates neuropathic pain by modulating programmed death-ligand 1 (PD-L1) in spinal microglia. This mechanism involves promoting M2-like polarization and inhibiting the MAPK pathway for reduced inflammation.
Area of Science:
- Neuroscience
- Immunology
- Pain Research
Background:
- Neuropathic pain is a debilitating condition with limited therapeutic options.
- Spinal microglia activation, particularly the M1/M2 phenotype balance, is crucial in pain progression.
- Programmed death-ligand 1 (PD-L1) is implicated in microglial polarization, influencing neuropathic pain.
Purpose of the Study:
- To investigate the role of PD-L1 in electroacupuncture (EA)-induced analgesia.
- To elucidate the underlying molecular mechanisms of EA and PD-L1 in neuropathic pain.
- To explore PD-L1 as a potential therapeutic target for neuropathic pain.
Main Methods:
- Spinal nerve ligation (SNL) in rats and lipopolysaccharide (LPS)-stimulated BV2 microglial cells were used as models.
- Behavioral assessments included mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL).
- Molecular analyses involved transmission electron microscopy, ELISA, flow cytometry, immunofluorescence, and Western blot to assess PD-L1, PD-1, M1/M2 markers, and MAPK signaling.
Main Results:
- EA treatment significantly increased pain thresholds and improved myelin structure in SNL rats.
- EA promoted PD-L1 and PD-1 expression, inhibited the MAPK pathway, and shifted microglial polarization from M1 to M2 phenotype.
- PD-L1 knockdown reversed EA's analgesic effects and exacerbated M1 polarization and inflammation in LPS-treated cells.
Conclusions:
- EA exerts analgesic effects by upregulating PD-L1, which promotes M2 microglial polarization and inhibits the MAPK pathway.
- This process reduces neuroinflammation and neuronal excitability, offering a novel therapeutic strategy for neuropathic pain.
- Targeting PD-L1 presents a promising avenue for developing effective treatments for neuropathic pain.
