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在BRCC3-介导的NLRP3脱化促进炎症体激活和动脉样硬化

Mustafa Yalcinkaya¹, Wenli Liu¹, Leigh-Anne Thomas^2,3,4,5

¹Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY (M.Y., W.L., T.X., S.A., M.W., N.W., I.T., A.R.T.).

|October 2, 2023

概括

Tet2 缺乏和高胆固醇通过JNK1信号激活NLRP3炎症体,促进动脉样硬化. 抑制BRCC3在小鼠和人类细胞中逆转了这些效应,提供了新的心血管疾病治疗策略.

科学领域:

免疫学
心血管生物学
表观遗传学

背景情况:

克隆性造血 (CH) 是心血管疾病的危险因素,可能由巨炎症体介导.
在缺乏Tet2的CH模型中,NLRP3炎症酶在动脉样硬化中起作用.
Tet2 缺乏影响表观遗传修饰,但其与巨炎细胞激活的联系尚不清楚.

研究的目的:

研究Tet2缺陷巨细胞中NLRP3炎症酶激活的机制.
探索表观遗传修饰在这个过程中的作用.
评估向该途径在与Tet2-CH相关的动脉样硬化中的治疗潜力.

主要方法:

在体外研究中使用了胆固醇含量高的Tet2缺乏的小鼠和人类巨细胞.
使用高胆固醇的Ldlr-/-小鼠在体内模型化Tet2CH.
研究了JNK1信号,DUSP10表达和BRCC3活动.

主要成果:

Tet2 缺乏和胆固醇协同增加了JNK1酸化和NLRP3炎症酶激活.
这与促进物甲基化增加和DUSP10表达减少有关.
通过BRCC3介导的NLRP3脱是关键的;在小鼠和人体细胞中,用holomycin抑制动脉样硬化和NETosis.

结论:

高胆固醇血症和Tet2缺乏症在JNK1激活和BRCC3介导的NLRP3激活上趋同.
这一途径对Tet2CH中的心血管疾病具有治疗意义.
针对BRCC3提供了一个潜在的治疗策略.

关键词:

动脉样硬化克隆性血液形成细胞外陷高胆固醇血症炎症体中性粒细胞化

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