Downregulation of lncRNA FIRRE relieved the neuropathic pain of female mice by suppressing HMGB1 expression
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Downregulation of lncRNA FIRRE relieved the neuropathic pain of female mice by suppressing HMGB1 expression Yuanyuan Wen1 · Xiaochong Fan1 · Huilian Bu1 · Letian Ma1 · Cunlong Kong1 · Chen Huang1 · Yuming Xu2 Received: 17 December 2019 / Accepted: 15 June 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Long non-coding RNAs are novel regulators in neuropathic pain. In this study, we aimed to explore the role and the mechanism of lncRNA FIRRE in regulating the secretion of microglial cells-derived proinflammatory cytokines in neuropathic pain. The female mouse model of neuropathic pain was established by bilateral chronic constriction injury (CCI) surgery. The mouse primary microglial cells were induced by lipopolysaccharide (LPS). The interaction between FIRRE and high mobility group box 1 (HMGB1) was assessed by RNA immunoprecipitation, RNA pull-down, and ubiquitination assays. FIRRE expression was upregulated in the spinal cord tissue of female CCI mice and LPS-induced microglial cells. The concentrations of IL-1β, TNF-α, and IL-6 from LPS-induced microglial cells were reduced by FIRRE knockdown. FIRRE bound to HMGB1 and negatively regulated its protein level. The ubiquitination degradation of HMGB1 was promoted by FIRRE silence. The HMGB1 over-expression reversed the inhibitory effect of FIRRE silence on the secretion of IL-1β, TNF-α, and IL-6 from LPS-induced microglial cells. The in vivo experiment showed that FIRRE knockdown alleviated neuropathic pain of CCI female mice. Our findings indicated that lncRNA FIRRE downregulation inhibits the secretion of microglial cellsderived proinflammatory cytokines by decreasing HMGB1 expression, thereby relieving neuropathic pain of female mice. Keywords lncRNA FIRRE · Neuropathic pain · Proinflammatory cytokines · Microglial cells · HMGB1
Introduction Neuropathic pain is a type of chronic pain caused by nerve injury or diseases such as diabetes and cancers [1, 2]. The incidence of neuropathic pain is ranged from 6.9 to 10% and is increasing as the growing aging global population, elevated morbidity of diabetes, and improved survival of cancer chemotherapy [3, 4]. Usually, neuropathic pain persists a long time and significantly impairs the life quality of patients [5]. Although many attempts have been taken to treat neuropathic pain, limited success has been achieved due to the deficient understanding of the pathogenesis of neuropathic pain.
* Yuming Xu [email protected] 1
Department of Pain, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhongyuan District, Zhengzhou 450000, China
2
Microglial cells, the immune cells of the central nervous system (CNS), derive from mesodermal precursor cells and are widely distributed in the CNS [6]. Such cells can be activated after nerve injury [7]. Activated microglial cells exert brain defense function by removing dead cells and acting as immune or im
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