Astrocytic NDRG2 is critical in the maintenance of neuropathic pain
Astrocytic NDRG2 is critical in the maintenance of neuropathic pain
复制标题
星形胶质细胞 NDRG2 对于神经性疼痛的维持至关重要。
DOI：
10.1016/j.bbi.2020.07.009
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发表时间：
2020-10-01
影响因子：
15.1
通讯作者：
Tang, Jun
中科院分区：
文献类型：
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作者：
Cheng, Hao;Zhang, Lidong;Tang, Jun
星形胶质细胞的激活和突触谷氨酸代谢的异常与神经病理性疼痛(NP)的诱导和维持密切相关，但这种联系的确切机制尚不清楚。N-myc下游调节基因2(NDRG2)是一种新的肿瘤抑制蛋白和应激反应基因，参与了多种神经退行性疾病的发病过程。然而，它在伤害性信号转导中的作用很少被研究。在此，我们发现主要在中枢神经系统(CNS)星形胶质细胞表达的NDRG2在脊神经结扎(SNL)大鼠的脊髓中增加。鞘内注射NDRG2-RNAi-腺病毒抑制NDRG2可显著减轻SNL诱导的大鼠脊髓背角机械和温度超敏反应、星形细胞谷氨酸转运体1(GLT-1)表达升高和促炎细胞因子水平下调。此外，在脂多糖(LPS)刺激的新生大鼠原代星形胶质细胞培养中，抑制NDRG2显著逆转了内毒素诱导的星形胶质细胞的激活和GLT-1的表达减少。相反，携带NDRG2的腺病毒载体过表达NDRG2可导致大鼠星形胶质细胞激活、谷氨酸能神经传递异常和自发的伤害性反应。鞘内注射JAK/STAT3(JAK/STAT3)信号通路抑制剂AG490可显著减轻NDRG2过度表达大鼠脊髓背角的机械性和热敏性痛觉过敏，抑制反应性星形胶质细胞和恢复星形胶质细胞GLT-1的正常表达水平。综上所述，脊髓星形细胞NDRG2在NP的维持中起关键作用。此外，NDRG2通过JAK/STAT3信号通路调节GLT-1的表达，从而调节星形胶质细胞的激活和炎症反应。我们的研究结果提示NDRG2可能是治疗NP的一个新的治疗靶点。
Activation of astrocytes and abnormal synaptic glutamate metabolism are closely associated with the induction and maintenance of neuropathic pain (NP), but the exact mechanism underlying this association remains unclear. N-myc downstream-regulated gene 2 (NDRG2), a novel tumor-suppressor protein and stress-response gene, is involved in the pathogenesis of several neurodegenerative diseases. However, its role in nociceptive transduction has rarely been investigated. Here, we found that NDRG2, which was mainly expressed in the astrocytes in the central nervous system (CNS), was increased in the spinal cord of a spinal nerve ligation (SNL) rat model for NP. Suppression of NDRG2 by intrathecal injection of an NDRG2-RNAi-adenovirus significantly alleviated SNL-induced mechanical and thermal hypersensitivity, as well as elevated astrocytic glutamate transporter 1 (GLT-1) expression and downregulated pro-inflammatory cytokine levels, in the spinal dorsal horn of rats on Day 10 after SNL. Furthermore, in lipopolysaccharide (LPS)-stimulated primary astrocytic cultures derived from neonatal rats, inhibition of NDRG2 significantly reversed both the LPS-induced activation of astrocytes and decreased expression of GLT-1. By contrast, overexpression of NDRG2 by an adenoviral vector carrying NDRG2 resulted in astrocytic activation, aberrant glutamatergic neurotransmission, and spontaneous nociceptive responses in rats. Intrathecal injection of AG490, which is an inhibitor of the Janus tyrosine kinase and signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway, significantly attenuated both mechanical and thermal hyperalgesia, as well as inhibited reactive astrocytes and restored normal expression levels of astrocytic GLT-1, in the spinal dorsal horn of NDRG2-overexpression rats. In conclusion, spinal astrocytic NDRG2 is critical in the maintenance of NP. Moreover, NDRG2 modulates astrocytic activation and inflammatory responses via regulating GLT-1 expression through the JAK/STAT3 signaling pathway. Our findings suggested that NDRG2 could be a novel therapeutic target for the treatment of NP.