伊塔科纳酸和衍生物的电友性质调节IκBζ-ATF3炎症轴
Monika Bambouskova1, Laurent Gorvel1, Vicky Lampropoulou1
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Nature
|April 20, 2018
概括
通过抑制IκBζ诱导,调节免疫反应. 这种途径有可能治疗像牛皮这样的自身免疫性疾病.
科学领域:
- 免疫学
- 代谢调节
- 细胞应激反应
背景情况:
- 免疫反应受代谢调节的指导,炎症性巨细胞产生伊塔康酸盐.
- 伊塔康酸及其衍生物二甲基伊塔康酸 (DI) 是免疫调节代谢物,可选择性抑制某些细胞因子.
- 之前的研究将伊塔康酸与酸脱酶抑制相关联,但这并不能完全解释其免疫调节作用.
研究的目的:
- 确定伊塔科纳酸和DI对炎症的选择性影响背后的调节途径.
- 研究DI选择性调节炎症反应的机制.
主要方法:
- 研究 itaconate 和 DI 对细胞代谢和免疫信号的影响.
- 使用了Nrf2 (NFE2L2) 依赖和独立的反应测定.
- 确定了包括IκBζ和ATF3在内的关键调解器和调节途径.
- 在小鼠牛皮病模型中测试DI疗效.
主要成果:
- 伊塔科纳酸和DI诱导电友应力,与谷反应.
- 这种压力激活了Nrf2依赖和独立的反应.
- 电友应激可以选择性地抑制IκBζ蛋白的诱导,这是一个关键的二次转录反应.
- 鉴定出ATF3是这种Nrf2独立调节的媒介.
- 在皮病模型中,体内注射改善了IL-17-IκBζ驱动的皮肤病理.
结论:
- 伊塔科纳酸和DI通过电友应激和随后的IκBζ诱导的抑制产生免疫调节作用.
- DI-IκBζ调节轴独立于Nrf2并由ATF3进行介导.
- 针对DI-IκBζ途径为IL-17和IκBζ驱动的自身免疫性疾病提供了潜在的治疗策略.
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