Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs.
growth/differentiation factor 15
nonsteroidal anti-inflammatory drugs
nuclear factor erythroid 2-related factor 2
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
14 06 2022
14 06 2022
Historique:
received:
23
12
2021
revised:
08
03
2022
accepted:
21
04
2022
pubmed:
20
5
2022
medline:
18
6
2022
entrez:
19
5
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35588739
pii: S1074-7613(22)00186-8
doi: 10.1016/j.immuni.2022.04.015
pmc: PMC9205175
mid: NIHMS1810438
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Anti-Inflammatory Agents, Non-Steroidal
0
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
Prostaglandin-Endoperoxide Synthases
EC 1.14.99.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1082-1095.e5Subventions
Organisme : NIAID NIH HHS
ID : K08 AI128745
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI162645
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR007016
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests P.T., H.T., and H.H.L. were employees of NGM Biopharmaceuticals at the time this work was done and may hold stock or stock options in this company. All data are available in the main text or the supplementary materials.
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