氧化IL-33驱动COPD表皮病原体通过ST2独立的RAGE/EGFR信号复合体
Sam Strickson1,2, Kirsty F Houslay1,2, Victor A Negri1
1Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
The European respiratory journal
|July 13, 2023
概括
氧化型干白素-33 (IL-33ox) 通过激活一种与已知的受体ST2独立的新途径来驱动COPD的呼吸道重塑和粘液产生. 准这种IL-33ox通路可以逆转COPD相关的上皮功能障碍.
科学领域:
- 肺部医学 肺部医学
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
背景情况:
- 慢性阻塞性肺病 (COPD) 涉及呼吸道上皮损伤,修复和重塑.
- 通过其受体ST2发出信号的介素-33 (IL-33) 在呼吸道疾病中调解炎症.
- 氧化IL-33 (IL-33ox) 假设由于ST2结合减少,其活性有限.
研究的目的:
- 为了研究空气道上皮质中独立于ST2的IL-33ox的功能活动.
- 阐明IL-33ox在COPD病变发生过程中的作用.
主要方法:
- 使用了体外上皮损伤测定和健康和COPD上皮的3D空气-液体接口 (ALI) 细胞培养模型.
- 采用批量和单细胞RNA测序来分析IL-33ox和IL-33中和反应中的转录组变化.
- 评估了IL-33ox与上皮受体的相互作用.
主要成果:
- IL-33ox与呼吸道表皮上的高级糖化终产品 (RAGE) 和表皮生长因子受体 (EGFR) 的受体形成复合体.
- 这种ST2独立的通路激活会损害上皮层伤口的关闭,并诱导气道重塑.
- IL-33ox增加了产生粘液的细胞,并减少了上皮防御,模仿了COPD的特征;路径中和在COPD模型中逆转了这些效应.
结论:
- IL-33,RAGE和EGFR在呼吸道上皮上形成了一个ST2独立的通路.
- 这一途径控制着异常的上皮重塑和COPD特征的粘膜阻塞特征.
- 针对这种新的IL-33ox通路为COPD提供了潜在的治疗策略.
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