Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway.
Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway.
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小白菊内酯通过 NF-kappa B 和 STAT 1/3 信号通路调节 M1/M2 极化，促进脊髓损伤的修复
DOI：
10.1038/s41420-020-00333-8
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发表时间：
2020
影响因子：
7
通讯作者：
Jian C
中科院分区：
文献类型：
--
作者：
Gaojian T;Dingfei Q;Linwei L;Xiaowei W;Zheng Z;Wei L;Tong Z;Benxiang N;Yanning Q;Wei Z;Jian C
脊髓损伤（Spinal cord injury，SCI）是一种严重的神经系统疾病，目前尚无有效的治疗方法。神经炎症反应涉及小胶质细胞的活化和巨噬细胞的浸润，是脊髓损伤继发性损伤的主要发病机制，被认为是脊髓损伤的治疗靶点。据报道，Parthenolamine（PN）在发热、偏头痛、关节炎和浅表炎症中发挥抗炎作用;然而，PN在SCI治疗中的作用尚未阐明。在本研究中，我们发现PN可以促进小鼠脊髓功能的恢复，表现为增加BMS评分和减少脊髓损伤的空腔。免疫荧光染色实验证实，PN可促进轴突再生，增加髓鞘重建，减少硫酸软骨素形成，抑制瘢痕增生，抑制A1神经毒性反应性星形胶质细胞的活化，促进小胶质细胞/巨噬细胞从M1向M2极化转变。为了验证PN如何影响小胶质细胞/巨噬细胞极化，我们在小胶质细胞系BV-2中进行了体外机制研究。PN可显著降低LPS诱导的BV 2细胞M1极化，部分挽救LPS诱导的M2表型标志物表达的下降，但对IL-4诱导的M2极化无明显影响。进一步研究表明，PN可直接或间接抑制NF-κB信号通路，并通过降低HDAC 1的表达，增加STAT 1/3的乙酰化水平，抑制信号转导和转录激活因子1或3（STAT 1/3）的激活。总的来说，我们的研究表明，PN可能是创伤性SCI的一个有前途的策略。
Spinal cord injury (SCI) is a severe neurological disease; however, there is no effective treatment for spinal cord injury. Neuroinflammation involves the activation of resident microglia and the infiltration of macrophages is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Parthenolide (PN) has been reported to exert anti-inflammatory effects in fever, migraines, arthritis, and superficial inflammation; however, the role of PN in SCI therapeutics has not been clarified. In this study, we showed that PN could improve the functional recovery of spinal cord in mice as revealed by increased BMS scores and decreased cavity of spinal cord injury in vivo. Immunofluorescence staining experiments confirmed that PN could promote axonal regeneration, increase myelin reconstitution, reduce chondroitin sulfate formation, inhibit scar hyperplasia, suppress the activation of A1 neurotoxic reactive astrocytes and facilitate shift from M1 to M2 polarization of microglia/macrophages. To verify how PN exerts its effects on microglia/macrophages polarization, we performed the mechanism study in vitro in microglia cell line BV-2. PN could significantly reduce M1 polarization in BV2 cells and partially rescue the decrease in the expression of M2 phenotype markers of microglia/macrophage induced by LPS, but no significant effect on M2 polarization stimulated with IL-4 was observed. Further study demonstrated PN inhibited NF-κB signal pathway directly or indirectly, and suppressed activation of signal transducer and activator of transcription 1 or 3 (STAT1/3) via reducing the expression of HDAC1 and subsequently increasing the levels of STAT1/3 acetylation. Overall, our study illustrated that PN may be a promising strategy for traumatic SCI.