ZBTB20 mediates stress-induced visceral hypersensitivity via activating the NF-κB/transient receptor potential channel pathway
ZBTB20 mediates stress-induced visceral hypersensitivity via activating the NF-κB/transient receptor potential channel pathway
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DOI：
10.1111/nmo.14718
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发表时间：
2023-11-27
影响因子：
3.5
通讯作者：
Chen，Sheng-Liang
中科院分区：
文献类型：
--
作者：
Luo，Qing-Qing;Cheng，Li;Chen，Sheng-Liang
背景心理应激是肠易激综合征内脏高敏感性（VH）的主要诱因.锌指蛋白ZBTB 20（ZBTB 20）通过调节瞬时受体电位（TRP）通道参与躯体伤害感受，但其在VH发生中的作用尚不清楚。本研究旨在探讨ZBTB 20/TRP通道轴在应激诱导的VH中的作用。鞘内施用靶向ZBTB 20的小干扰RNA（siRNA）。给予TRP通道、应激激素受体和核因子κ B（NF-κB）抑制剂。记录内脏对结直肠扩张的反应。解剖背根神经节（DRG）进行Western印迹、免疫共沉淀和染色质免疫沉淀。Key ResultsWAS诱导的VH被TRPV 1、TRPA 1或TRPM 8的抑制剂抑制，这些通道在L 6-S2 DRG中的表达增强。糖皮质激素受体或β2-肾上腺素能受体的抑制剂抵消了WAS诱导的VH和TRP通道表达。同时，WAS诱导DRG中应激激素依赖性ZBTB 20表达和NF-κB活化。鞘内注射ZBTB 20 siRNA或NF-κB抑制剂可抑制WAS引起的效应。在培养的DRG衍生神经元中，应激激素促进ZBTB 20的核转位，其先于p65核转位。而且，ZBTB 20 siRNA抑制应激激素引起的NF-κB活化。结论ZBTB 20通过激活NF-κB/TRP通道途径介导应激诱导的VH。
BackgroundPsychological stress is a major trigger for visceral hypersensitivity (VH) in irritable bowel syndrome. The zinc finger protein ZBTB20 (ZBTB20) is implicated in somatic nociception via modulating transient receptor potential (TRP) channels, but its role in the development of VH is unclear. This study aimed to investigate the role of ZBTB20/TRP channel axis in stress‐induced VH.MethodsRats were subjected to water avoidance stress (WAS) for 10 consecutive days. Small interfering RNA (siRNA) targeting ZBTB20 was intrathecally administered. Inhibitors of TRP channels, stress hormone receptors, and nuclear factor kappa‐B (NF‐κB) were administered. Visceromotor response to colorectal distension was recorded. Dorsal root ganglia (DRGs) were dissected for Western blot, coimmunoprecipitation, and chromatin immunoprecipitation. The DRG‐derived neuron cell line was applied for specific research.Key ResultsWAS‐induced VH was suppressed by the inhibitor of TRPV1, TRPA1, or TRPM8, with enhanced expression of these channels in L6‐S2 DRGs. The inhibitor of glucocorticoid receptor or β2‐adrenergic receptor counteracted WAS‐induced VH and TRP channel expression. Concurrently, WAS‐induced stress hormone‐dependent ZBTB20 expression and NF‐κB activation in DRGs. Intrathecally injected ZBTB20 siRNA or an NF‐κB inhibitor repressed WAS‐caused effect. In cultured DRG‐derived neurons, stress hormones promoted nuclear translocation of ZBTB20, which preceded p65 nuclear translocation. And, ZBTB20 siRNA suppressed stress hormone‐caused NF‐κB activation. Finally, WAS enhanced p65 binding to the promoter of TRPV1, TRPA1, or TRPM8 in rat DRGs.Conclusions and InferencesZBTB20 mediates stress‐induced VH via activating NF‐κB/TRP channel pathway in nociceptive sensory neurons.