葡萄糖皮质体受体通过与P63的功能相互作用和表皮皮质角质细胞中自身隐性信号传递来控制亚托皮性皮炎炎症
Lisa M Sevilla1, Omar Pons-Alonso1, Andrea Gallego1
1Instituto de Biomedicina de Valencia (IBV-CSIC), Department of Pathology and Molecular and Cell Therapy, Valencia, Spain.
Cell death & disease
|July 28, 2024
概括
葡萄糖皮质类受体 (GR) 损失通过与皮肤细胞中的转录因子p63相互作用,导致亚托皮炎 (AD). 这种相互作用促进了AD特征的炎症和表皮屏障缺陷.
科学领域:
- 皮肤病学 皮肤病学
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 亚托皮炎 (AD) 是一种慢性炎症性皮肤疾病,具有表皮屏障缺陷和免疫失调.
- 葡萄糖皮质类药物 (GCs) 治疗阿尔茨海默病,但它们的精确机制,特别是关于局部GC信号传递的机制,仍然不清楚.
- 在炎症性皮肤疾病中观察到降低的葡萄糖皮质受体 (GR) 水平,但它们在AD病变发生中的作用仍在争论中.
研究的目的:
- 为了阐明细胞类型特定的GR在角质细胞中的互动体.
- 在AD中调查GR和转录因子p63之间的功能关系.
- 确定GR信号在状细胞对AD模仿细胞因子的反应中的作用.
主要方法:
- 内源蛋白质的快速免疫沉,然后进行质谱 (MS) 检测以确定GR相互作用体.
- 甲治疗以评估GR相互作用组的变化.
- 在各种条件下 (例如,IL4/IL13刺激,GR淘汰) 分析GR和p63结合和表达在培养的角质细胞和人类表皮等效物 (HEE) 中.
主要成果:
- 德甲治疗增加了与染色质结合的GR相互作用体的数量,这些相互作用体富含了p53/p63信号通路.
- TP63被确定为直接的GR目标,IL4/IL13刺激降低了GR,同时增加了角质细胞中的p63水平,反映了AD病变.
- 在HEEs中,GR knockdown诱导了类似AD的特征,包括增生和异常分化,以及炎症性细胞因子的自身分泌产生增加.
结论:
- 失去GR在亚托皮性皮肤炎的发病过程中起着起因作用.
- 在表皮皮质角质细胞中GR和p63之间的功能相互作用在AD中至关重要.
- 由于GR缺乏,AD通过自身隐性信号传递和表皮平衡的破坏来促进AD.
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