Sensory neuron-specific long noncoding RNA in small non-peptidergic dorsal root ganglion neurons selectively impairs nerve injury-induced mechanical hypersensitivity.
Sensory neuron-specific long noncoding RNA in small non-peptidergic dorsal root ganglion neurons selectively impairs nerve injury-induced mechanical hypersensitivity.
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DOI：
10.1016/j.lfs.2023.122120
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发表时间：
2023-09
期刊：
影响因子：
6.1
通讯作者：
Bing Wang;Yingping Liang;Alex Bekker;Huijuan Hu;Yuan-Xiang Tao
中科院分区：
文献类型：
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作者：
Bing Wang;Yingping Liang;Alex Bekker;Huijuan Hu;Yuan-Xiang Tao
神经损伤引起的机械性超敏反应是神经病理性疼痛患者的主要临床症状之一。了解这种症状的分子机制对于开发有效的治疗方法至关重要。本研究旨在探讨感觉神经元特异性长非编码RNA是否主要在小的非肽能背根神经节（DRG）神经元中表达的SS-lncRNA（SS-lncRNA）修复神经损伤诱导的机械超敏性。在Mrgprd表达的DRG神经元中的SS-lncRNAd下调调节显著逆转了脊神经结扎（SNL）诱导的这些DRG神经元中钙激活钾通道亚家族N成员1（KCNN 1）的减少，并减轻了SNL诱导的机械超敏反应，而不影响SNL诱导的热和冷伤害性超敏反应，在同侧。相反，在Mrgprd表达的DRG神经元中模仿SS-lncRNAdown调节减少了这些DRG神经元中的基础KCNN 1表达，并在双侧产生了对机械刺激的增强反应，但对热刺激和冷刺激没有。机械地说，SS-lncRNAdown调节导致其与赖氨酸特异性脱甲基酶6 B（KDM 6 B）的结合减少，从而减少KDM 6 B向Kcnn 1启动子的募集，并增加H3 K27 me 3在受损DRG中该启动子中的富集。诱导的机械超敏反应可能是通过沉默KCNN 1表达引起的KDM 6 B门控增加H3 K27 me 3富集在这些神经元中的Kcnn 1启动子。
AimsNerve injury-induced mechanical hypersensitivity is one of major clinical symptoms in neuropathic pain patients. Understanding molecular mechanisms underlying this symptom is crucial for developing effective therapies. The present study was to investigate whether sensory neuron-specific long noncoding RNA (SS-lncRNA) predominantly expressed in small non-peptidergic dorsal root ganglion (DRG) neurons repaired nerve injury-induced mechanical hypersensitivity.Materials and methodsSS-lncRNAdownregulation in the mas-related G protein-coupled receptor member D (Mrgprd)-expressed DRG neurons was rescued and mimicked by crossbreeding MrgprdCreERT2/+lines with Rosa26SS-lncRNAknock-in mice andSS-lncRNAfl/flmice, respectively, followed by tamoxifen injection.Key findingsRescuingSS-lncRNAdownregulation in the Mrgprd-expressed DRG neurons significantly reversed the spinal nerve ligation (SNL)-induced reduction of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in these DRG neurons and alleviated the SNL-induced mechanical hypersensitivity, without affecting the SNL-induced heat and cold nociceptive hypersensitivities, on the ipsilateral side. Conversely, mimickingSS-lncRNAdownregulation in the Mrgprd-expressed DRG neurons reduced basal KCNN1 expression in these DRG neurons and produced the enhanced response to mechanical stimulation, but not thermal and cold stimuli, on bilateral sides. Mechanistically,SS-lncRNAdownregulation caused a reduction in its binding to lysine-specific demethylase 6B (KDM6B) and consequent recruitment of less KDM6B toKcnn1promoter and an increase of H3K27me3 enrichment in this promoter in injured DRG.SignificanceOur findings suggest thatSS-lncRNAdownregulation in small non-peptidergic sensory neurons is required specifically for nerve injury-induced mechanical hypersensitivity likely through silencing KCNN1 expression caused by KDM6B-gated increase of H3K27me3 enrichment inKcnn1promoter in these neurons.