Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs.
Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs.
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DOI：
10.1016/j.immuni.2022.04.015
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发表时间：
2022-06-14
期刊：
影响因子：
32.4
通讯作者：
Wang, Andrew
中科院分区：
文献类型：
--
作者：
Eisenstein, Anna;Hilliard, Brandon K.;Pope, Scott D.;Zhang, Cuiling;Taskar, Pranali;Waizman, Daniel A.;Israni-Winger, Kavita;Tian, Hui;Luan, Harding H.;Wang, Andrew
非甾体抗炎药（NSAID）抑制环氧合酶（考克斯）酶，因其抗炎特性而广泛使用。然而，单独的考克斯抑制不能解释NSAID使用的许多临床结果。在原代人和鼠骨髓细胞中筛选常用的NSAID表明，NSAID可以通过其诱导生长/分化因子15（GDF 15）的能力来区分，而不依赖于考克斯特异性。使用遗传学和药理学方法，NSAID介导的GDF 15诱导依赖于髓系细胞中核因子红细胞2相关因子2（NRF 2）的激活。通过NRF 2分子伴侣的半胱氨酸151的传感，Kelch样ECH相关蛋白1（KEAP 1）是NSAID激活NRF 2和随后的体外和体内抗炎作用所需的。在痛风和内毒素血症小鼠模型中，骨髓特异性NRF 2缺失废除了NSAID介导的组织保护作用。这突出了一个非经典的NRF 2依赖性机制的抗炎活性的一个子集常用的NSAID。非甾体抗炎药（NSAID）的使用是普遍存在的。在此，Eisenstein等人通过激活转录因子核因子红细胞2相关因子2（NRF 2）确定了NSAID抗炎活性的非经典作用机制。在内毒素血症和痛风模型中，吲哚美辛以NRF 2依赖性方式改善炎症。
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce Growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on activation of Nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is ubiquitous. Herein, Eisenstein et al identify a noncanonical mechanism of action for the anti-inflammatory activity of NSAIDs through activation of the transcription factor, Nuclear factor erythroid 2-related factor 2 (NRF2). In endotoxemia and gout models, indomethacin improved inflammation in an NRF2-dependent manner.
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DOI：
10.1056/nejmoa1306033
发表时间：
2013-12-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
de Zeeuw D;Akizawa T;Audhya P;Bakris GL;Chin M;Christ-Schmidt H;Goldsberry A;Houser M;Krauth M;Lambers Heerspink HJ;McMurray JJ;Meyer CJ;Parving HH;Remuzzi G;Toto RD;Vaziri ND;Wanner C;Wittes J;Wrolstad D;Chertow GM;BEACON Trial Investigators
通讯作者：
BEACON Trial Investigators
影响因子：
9.3
作者：
Foresti, Roberta;Bains, Sandip K.;Motterlini, Roberto
通讯作者：
Motterlini, Roberto
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
2.2
作者：
Abram CL;Roberge GL;Hu Y;Lowell CA
通讯作者：
Lowell CA
影响因子：
168.9
作者：
da Costa, Bruno R.;Reichenbach, Stephan;Trelle, Sven
通讯作者：
Trelle, Sven