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NRF2通过转录调节卡斯帕酶-11的表达,以激活自性缺陷肝细胞释放的HMGB1

Bilon Khambu^1,2, Genxiang Cai³, Gang Liu^4,5

¹Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LO, USA. bkhambu@tulane.edu.

Cell death discovery

|July 28, 2023

概括

在自性缺陷细胞中持续的NRF2激活可提高Caspase-11的调节,通过非Gasdermin D途径驱动HMGB1释放和软膜增殖,揭示了一种新的炎症酶激活机制.

科学领域:

细胞生物学细胞生物学
免疫学免疫学免疫学
病理学病理学病理学

背景情况:

高流动性组盒1 (HMGB1) 是损伤相关分子模式 (DAMP) 分子,在受伤或压力期间释放出来,导致炎症.
从巨细胞中释放的活性HMGB1涉及炎症细胞和Gasdermin D孔形成.
自缺乏的肝细胞也依赖于炎症体释放HMGB1,但激活机制尚不清楚.

研究的目的:

阐明导致HMGB1在自缺陷肝细胞中释放的炎酶激活机制.
研究转录因子NRF2在这个过程中的作用.

主要方法:

染色体免疫沉 (CHIP) 试验用于评估NRF2与Caspase-11促进体的结合.
基于Luciferase的记者测试来测量转录活动.
在自性缺陷小鼠模型中对Caspase-11和Gasdermin D进行遗传删除研究.
分析HMGB1释放和结状细胞增殖的情况.

主要成果:

在自性缺陷条件下持续的NRF2激活在转录上调 Caspase-11.
NRF2直接与卡斯帕酶-11促进体结合,增加其表达.
基因删除Caspase-11,但不包括Gasdermin D,抑制HMGB1释放和在缺血自的肝脏中状细胞的增殖.
HMGB1的释放独立于Gasdermin D裂变发生,这表明了另一种释放机制.

结论:

NRF2在转录上调Caspase-11中发挥着新的作用,导致炎症酶激活.
这种NRF2-Caspase-11轴促进HMGB1释放和通过非加斯德明D-依赖的途径在自缺陷肝细胞中通过病理性软膜增殖.
这些发现揭示了活性HMGB1释放的新机制.

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