Chronic Pain After Spinal Cord Injury: Is There a Role for Neuron-Immune Dysregulation?

Chambel, Sílvia Sousa; Tavares, Isaura; Cruz, Carlos Oliveira

doi:10.3389/fphys.2020.00748

Cited by 23 publications

(26 citation statements)

References 93 publications

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“…Previous reports have demonstrated that neuropathic pain can accompany SCI [ 40 ]. Here, we confirmed mechanical allodynia using a dynamic plantar test [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

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Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents

Lee

Yeum

et al. 2021

IJMS

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Stem cell therapy is one of the most promising candidate treatments for spinal cord injury. Research has shown optimistic results for this therapy, but clinical limitations remain, including poor viability, engraftment, and differentiation. Here, we isolated novel peripheral nerve-derived stem cells (PNSCs) from adult peripheral nerves with similar characteristics to neural-crest stem cells. These PNSCs expressed neural-crest specific markers and showed multilineage differentiation potential into Schwann cells, neuroglia, neurons, and mesodermal cells. In addition, PNSCs showed therapeutic potential by releasing the neurotrophic factors, including glial cell-line-derived neurotrophic factor, insulin-like growth factor, nerve growth factor, and neurotrophin-3. PNSC abilities were also enhanced by their development into spheroids which secreted neurotrophic factors several times more than non-spheroid PNSCs and expressed several types of extra cellular matrix. These features suggest that the potential for these PNSC spheroids can overcome their limitations. In an animal spinal cord injury (SCI) model, these PNSC spheroids induced functional recovery and neuronal regeneration. These PNSC spheroids also reduced the neuropathic pain which accompanies SCI after remyelination. These PNSC spheroids may represent a new therapeutic approach for patients suffering from SCI.

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“…Previous reports have demonstrated that neuropathic pain can accompany SCI [ 40 ]. Here, we confirmed mechanical allodynia using a dynamic plantar test [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

“…Mechanical allodynia is only one form of neuropathic pain and the causes of neuropathic pain after SCI are not known, but those suspected include immune responses, glial cells, and myelin degeneration [ 40 , 42 , 43 , 44 ]. Here, we confirmed an inflammatory response using the markers CD68 and IL-1β ( Figure 5 B).…”

Section: Resultsmentioning

confidence: 99%

Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents

Lee

Yeum

et al. 2021

IJMS

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“…Previous studies have argued that Nep is attributed to a dysregulation and hyperexcitability of primary afferent pathways (6). However, recent evidence suggests that neuroinflammation may also be involved in Nep after SCI (7). The activation of microglia is thought to contribute to the maintenance of Nep post-SCI (8).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Previous studies have argued that Nep is attributed to a dysregulation and hyperexcitability of primary afferent pathways [6]. However, recent evidence suggests that neuroin ammation may also be involved in neuropathic pain after SCI [7]. The activation of microglia is thought to contribute to the maintenance of Nep post-SCI [8].…”

Section: Introductionmentioning

confidence: 99%

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

Shi

Kong

Sun

et al. 2021

Preprint

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Background Traumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep) that remains uncured yet. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment, and the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of research has begun to investigate the effect of PD-L1 on macrophages and microglia. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we tested the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through macrophages and microglia. Methods The mice SCI model was employed 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. Results In present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia. PD-L1 knockout (KO) mice showed poor locomotor recovery and 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. Conclusions Our observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for prevention and treatment of this traumatic condition.

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Chronic Pain After Spinal Cord Injury: Is There a Role for Neuron-Immune Dysregulation?

Cited by 23 publications

References 93 publications

Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents

Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents

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

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

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