PD-L1 Improves Motor Function and Alleviates Neuropathic Pain in Male Mice After Spinal Cord Injury by Inhibiting MAPK Pathway

Abstract

BackgroundTraumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep), which has not yet been effectively cured. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment. However, the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of researches have begun to investigate the effect of PD-L1 on macrophages and microglia in recent years. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we proposed the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through regulating macrophages and microglia.MethodsThe mice SCI model was established to determine the changes in expression patterns of PD-L1. Meanwhile, we constructed PD-L1 knockout mice to observe differences in functional recovery and phenotypes of macrophages/microglia post-SCI.ResultsIn present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia at the injury epicenter. PD-L1 knockout (KO) mice showed worse locomotor recovery and more serious pathological pain compared with wild-type (WT) mice. Furthermore, deletion of PD-L1 significantly increased the polarization of M1-like macrophages/microglia. Mechanistic analysis revealed that PD-L1 may improve functional outcomes following SCI by inhibiting phosphorylation of p38 and ERK1/2.ConclusionsOur observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for the prevention and treatment of this traumatic condition.

Inflammatory biomarkers in patients with painful knee osteoarthritis: exploring the potential link to chronic postoperative pain after total knee arthroplasty—a secondary analysis

“…3,10,22 In addition, programmed cell death ligand-1 (PD-L1), a factor produced by cancer cells, has been reported in preclinical studies to be involved in analgesia and hyperalgesia processes and regulate neuronal activity. 11,34 Furthermore, although STAMBP, a member of the Jab1/MPN metalloenzyme (JAMM) family of deubiquitinating enzymes (DUBs), 14 has not been directly associated with pain processes in previous research, analysis of the presented data revealed an alteration of STAMBP in patients with knee OA. 24 Previous studies have highlighted the involvement of STAMBP in the regulation of inflammatory cascade by facilitating the maturation of inflammatory cytokines.…”

Circular RNA SMEK1 promotes neuropathic pain in rats through targeting microRNA-216a-5p to mediate Thioredoxin Interacting Protein (TXNIP) expression

“…It was in this work found that overexpressed circSMEK1 promotes NP development and spinal cord inflammation in CCI rats. When NP occurs, the phenotypes of microglia usually change, with an increase in pro-inflammatory microglia [ 30 , 31 ]. In this work, it was manifested that overexpressed circSMEK1 increased CD68 expression in CCI rats and LPS-treated microglia while inhibited CD206 expression.…”

Engineering of M2 Macrophages‐Derived Exosomes via Click Chemistry for Spinal Cord Injury Repair

“…The functional rehabilitation of SCI mice after different treatments was also evaluated by MEP as previously described. [ 42 ]…”

“…The functional rehabilitation of SCI mice after different treatments was also evaluated by MEP as previously described. [42] Histological Staining and Immunofluorescence Labeling: At designated times, mice were euthanized and transcardially perfused with saline followed by 4% paraformaldehyde. Then their spinal cords were harvested, fixed by 4% paraformaldehyde, embedded in paraffin, and sectioned into 20 μm thickness.…”