Yi Zi-Long, Lu Jin-Nan, Zhu Jin-Jin, He Tian-Tian, Xu Yi-Ran, Huang Zi-Wei, Li Yong-Chang, Xu Guang-Yin
Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou UniversityZhengzhou University.
This institution is not connected to Ringgold. Search again and select an institution from the dropdown to connect the institution Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of NeuroscienceSoochow University.
Mol Pain. 2024 May 25;20:17448069241260349. doi: 10.1177/17448069241260349.
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.
肠易激综合征（IBS）是一种常见的功能性胃肠疾病，其特征为慢性内脏疼痛，病因复杂，治疗具有挑战性。尽管越来越多的证据支持中枢神经系统敏化参与内脏疼痛的发生发展，但其确切的分子机制仍未完全明确。在本研究中，我们强调了赖氨酸特异性去甲基化酶6B（KDM6B）在前扣带回皮质（ACC）中对慢性内脏疼痛的关键调节作用。为模拟临床IBS情况，我们使用了新生小鼠母婴分离（NMD）模型。我们的结果表明，NMD可诱导小鼠出现慢性内脏疼痛和焦虑样行为。值得注意的是，NMD小鼠ACC中KDM6B的蛋白表达水平显著升高，导致H32K7me3表达水平降低。免疫荧光染色显示，KDM6B主要与ACC中的神经元共定位，在小胶质细胞和星形胶质细胞中含量极少。向NMD小鼠的ACC注射GSK-J4（一种KDM6B特异性抑制剂），可显著减轻慢性内脏疼痛和焦虑样行为，同时NR2B表达水平也显著降低。染色质免疫沉淀分析进一步表明，KDM6B通过影响H3K27me3的去甲基化来调节NR2B的表达。总之，我们的研究结果强调了KDM6B在调节NMD小鼠慢性内脏疼痛和焦虑样行为中的关键作用。这些见解为进一步理解IBS涉及的分子途径提供了基础，并可能为靶向治疗干预铺平道路。
