Niu Qin, Xing Fei, Gu Han-Wen, Bai Liying, Zhang Jian, Yuan Jing-Jing, Mao Yuan-Yuan, Li Zhi-Song, Zhang Wei, Xu Ji-Tian
Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, P.R. China; Department of Anaesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, P.R. China.
Department of Anaesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, P.R. China.
Neuroscience. 2020 Apr 15;432:174-187. doi: 10.1016/j.neuroscience.2020.02.041. Epub 2020 Mar 3.
Myeloid zinc finger 1 (MZF1) belongs to the Kruppel family of zinc-finger transcription factors. Recent studies have demonstrated that in dorsal root ganglion (DRG) neurons, MZF1 is involved in the development and maintenance of neuropathic pain. However, the role of MZF1 in inflammatory pain still remains unknown. In the present study, the mechanism of MZF1 in chronic inflammatory pain was investigated in rats received an intraplantar injection of complete Freund's adjuvant (CFA). Subsequently, a series of assays including Western blotting, qRT-PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) were performed. We found that CFA led to MZF1 upregulation in ipsilateral L4/5 DRGs. Pre- and post-microinjection of MZF1 siRNA into the ipsi-L5 DRG blocked the development of CFA-induced chronic inflammatory pain and alleviated the mechanical allodynia and thermal hyperalgesia in the maintenance phase. CFA also increased MMP-2/9 and Nav1.8 expression but reduced voltage-gated potassium 1.2 (Kv1.2) and Cav1.2 expression in L4/L5 DRGs. Microinjection of MZF1 siRNA into DRG diminished the CFA-induced changes in MMP-2/9 and Kv1.2 expression. However, the expressions of Nav1.8 and Cav1.2 were not changed by the treatment. Double immunofluorescence staining showed that MMP-2/9 and Kv1.2 were co-localized with MZF1 in DRGs. The ChIP-PCR results revealed that MZF1 binds directly to the promoter region of MMP-2/9 gene. Together, the above results imply that upregulation of MZF1 in DRGs might contribute to the development and maintenance of CFA-induced chronic inflammatory pain by regulating MMP-2/9 and Kv1.2 expression. Targeting DRG-localized MZF1 might be a promising therapeutic strategy for the treatment of chronic inflammatory pain in the clinic.
髓样锌指蛋白1（MZF1）属于锌指转录因子的克鲁ppel家族。最近的研究表明，在背根神经节（DRG）神经元中，MZF1参与神经性疼痛的发生和维持。然而，MZF1在炎性疼痛中的作用仍然未知。在本研究中，在足底注射完全弗氏佐剂（CFA）的大鼠中研究了MZF1在慢性炎性疼痛中的机制。随后，进行了一系列检测，包括蛋白质免疫印迹、qRT-PCR、免疫组织化学和染色质免疫沉淀（ChIP）。我们发现CFA导致同侧L4/5背根神经节中MZF1上调。在同侧L5背根神经节显微注射MZF1 siRNA前后，可阻断CFA诱导的慢性炎性疼痛的发展，并减轻维持期的机械性异常性疼痛和热痛觉过敏。CFA还增加了L4/L5背根神经节中MMP-2/9和Nav1.8的表达，但降低了电压门控钾通道1.2（Kv1.2）和Cav1.2的表达。向背根神经节显微注射MZF1 siRNA可减少CFA诱导的MMP-2/9和Kv1.2表达变化。然而，Nav1.8和Cav1.2的表达不受该处理的影响。双重免疫荧光染色显示，MMP-2/9和Kv1.2在背根神经节中与MZF1共定位。ChIP-PCR结果显示，MZF1直接结合MMP-2/9基因的启动子区域。综上所述，上述结果表明，背根神经节中MZF1的上调可能通过调节MMP-2/9和Kv1.2的表达，促进CFA诱导的慢性炎性疼痛的发生和维持。靶向背根神经节定位的MZF1可能是临床上治疗慢性炎性疼痛的一种有前景的治疗策略。
