转录因子
环氧合酶
药理学
体内
炎症
髓样
GDF15型
癌症研究
生物
体外
酶
免疫学
生物化学
基因
内分泌学
生物技术
作者
Anna Eisenstein,Brandon Hilliard,Scott D. Pope,Cuiling Zhang,Pranali Taskar,Daniel A. Waizman,Kavita Israni-Winger,Hui Tian,Harding H. Luan,Andrew Wang
出处
期刊:Immunity
[Elsevier]
日期:2022-06-01
卷期号:55 (6): 1082-1095.e5
被引量:22
标识
DOI:10.1016/j.immuni.2022.04.015
摘要
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 the 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.
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