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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PD-L1 通过抑制 MAPK 通路改善脊髓损伤后雄性小鼠的运动功能并减轻神经性疼痛
DOI：
10.3389/fimmu.2021.670646
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发表时间：
2021
影响因子：
7.3
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Kong F;Sun K;Zhu J;Li F;Lin F;Sun X;Luo X;Ren C;Lu L;Zhao S;Sun J;Wang Y;Shi J
研究背景创伤性脊髓损伤（Traumatic spinal cord injury，SCI）可引起严重的运动功能障碍和持续性中枢神经痛（central neuropathic pain，Nep），至今仍未得到有效治疗。程序性细胞死亡配体-1（PD-L1）通常由癌细胞产生，并有助于肿瘤微环境中的免疫抑制。然而，PD-L1在SCI后调节炎症反应和Nep中的作用仍不清楚。近年来，越来越多的研究开始研究PD-L1对巨噬细胞和小胶质细胞的影响。考虑到巨噬细胞/小胶质细胞在SCI后炎症反应中的关键作用，我们提出了PD-L1通过调节巨噬细胞和小胶质细胞促进SCI后运动和感觉功能恢复的假设。方法建立小鼠脊髓损伤模型，检测PD-L1表达模式的变化。同时，我们构建PD-L1基因敲除小鼠，观察SCI后巨噬细胞/小胶质细胞功能恢复和表型的差异。结果脊髓损伤后PD-L1表达明显上调，在损伤中心的巨噬细胞/小胶质细胞上表达明显增加。与野生型（WT）小鼠相比，PD-L1敲除（KO）小鼠表现出更差的运动恢复和更严重的病理性疼痛。此外，PD-L1的缺失显著增加了M1样巨噬细胞/小胶质细胞的极化。机制分析显示，PD-L1可能通过抑制p38和ERK 1/2的磷酸化来改善SCI后的功能结局。结论PD-L1参与了脊髓损伤的恢复过程，为脊髓损伤的预防和治疗提供了新的治疗策略。
Background Traumatic 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. Methods The 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. Results In 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. Conclusions Our 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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影响因子：
4.1
作者：
Lin, X.;Wang, M.;Xu, R.
通讯作者：
Xu, R.
影响因子：
9.3
作者：
Kong, Fan-Qi;Zhao, Shu-Jie;Fan, Jin
通讯作者：
Fan, Jin
影响因子：
3
作者：
Eck, JC;Nachtigall, D;Hodges, SD
通讯作者：
Hodges, SD
p38 MAPK，小胶质信号传导和神经性疼痛。
影响因子：
3.3
作者：
Ji, Ru-Rong;Suter, Marc R.
通讯作者：
Suter, Marc R.
影响因子：
5.3
作者：
Kong X;Gao J
通讯作者：
Gao J