Relationship of Inflammatory Cytokines From M1-Type Microglia/Macrophages at the Injured Site and Lumbar Enlargement With Neuropathic Pain After Spinal Cord Injury in the CCL21 Knockout (plt) Mouse
Relationship of Inflammatory Cytokines From M1-Type Microglia/Macrophages at the Injured Site and Lumbar Enlargement With Neuropathic Pain After Spinal Cord Injury in the CCL21 Knockout (plt) Mouse
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DOI：
10.3389/fncel.2019.00525
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发表时间：
2019-11-21
影响因子：
5.3
通讯作者：
Matsumine, Akihiko
中科院分区：
文献类型：
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作者：
Honjoh, Kazuya;Nakajima, Hideaki;Matsumine, Akihiko
脊髓损伤（SCI）导致正常感觉丧失，并经常导致神经性疼痛（NeP）。在多达80%的SCI患者中，慢性NeP在SCI病变处或以下发展，并且可能由活化的小胶质细胞和巨噬细胞释放的神经元兴奋性调节剂诱导。在SCI后的炎症反应中，经典活化（M1表型）或替代活化（M2表型）的不同小胶质细胞/巨噬细胞群体已引起极大兴趣。趋化因子最近在神经元-小胶质细胞通讯中也引起了人们的注意。CCL 21是一种激活中枢神经系统（CNS）中的小胶质细胞的趋化因子，并且仅在具有损伤或机械损伤的神经元中表达。在这项研究中，我们使用CCL 21表达缺陷的突变型（plt）小鼠的SCI模型，评估了SCI后NeP和小胶质细胞/巨噬细胞和炎性细胞因子在损伤部位和腰椎肿大处的表达。与野生型（C57 BL/6）小鼠相比，plt小鼠对SCI诱导的机械和热刺激超敏反应减轻，尽管运动功能没有差异。免疫组化和流式细胞术分析表明，小胶质细胞/巨噬细胞的表型是M1型占主导地位的两种类型的小鼠在病变部位和腰椎肿大。与野生型相比，在plt小鼠中观察到M1型小胶质细胞/巨噬细胞减少，而M2型小胶质细胞/巨噬细胞的数量在这些小鼠之间没有差异。在免疫印迹分析中，M1诱导的细胞因子[肿瘤坏死因子-α（TNF-α），干扰素-γ（IFN-γ）]的表达在plt小鼠中降低，而M2诱导的细胞因子白细胞介素-4（IL-4，IL-10）在两种类型的小鼠中没有差异。这项研究的结果表明，通过减少M1型小胶质细胞/巨噬细胞在损伤部位和腰椎肿大的数量来抑制炎性细胞因子的表达与提供减少NeP的环境有关。这些发现可能有助于设计新的治疗方法来减轻SCI后的NeP。
Spinal cord injury (SCI) causes loss of normal sensation and often leads to debilitating neuropathic pain (NeP). Chronic NeP develops at or below the SCI lesion in as many as 80% of patients with SCI and may be induced by modulators of neuronal excitability released from activated microglia and macrophages. In the inflammatory response after SCI, different microglia/macrophage populations that are classically activated (M1 phenotype) or alternatively activated (M2 phenotype) have become of great interest. Chemokines have also recently attracted attention in neuron-microglia communication. CCL21 is a chemokine that activates microglia in the central nervous system (CNS) and is expressed only in neurons with an insult or mechanical injury. In this study using an SCI model in mutant (plt) mice with deficient CCL21 expression, we assessed post-SCI NeP and expression of microglia/macrophages and inflammatory cytokines at the injured site and lumbar enlargement. SCI-induced hypersensitivities to mechanical and thermal stimulation were relieved in plt mice compared with those in wild-type (C57BL/6) mice, although there was no difference in motor function. Immunohistochemistry and flow cytometry analysis showed that the phenotype of microglia/macrophages was M1 type-dominant in both types of mice at the lesion site and lumbar enlargement. A decrease of M1-type microglia/macrophages was seen in plt mice compared with wild-type, while the number of M2-type microglia/macrophages did not differ between these mice. In immunoblot analysis, expression of M1-induced cytokines [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma)] was decreased in plt mice, while that of M2-induced cytokines interleukin-4 (IL-4, IL-10) did not differ in the two types of mice. The results of this study indicate that suppression of expression of inflammatory cytokines by decreasing the number of M1-type microglia/macrophages at the injured site and lumbar enlargement is associated with provision of an environment for reduction of NeP. These findings may be useful for the design of new therapies to alleviate NeP after SCI.