PMID- 35588739
OWN - NLM
STAT- MEDLINE
DCOM- 20220617
LR  - 20230616
IS  - 1097-4180 (Electronic)
IS  - 1074-7613 (Print)
IS  - 1074-7613 (Linking)
VI  - 55
IP  - 6
DP  - 2022 Jun 14
TI  - Activation of the transcription factor NRF2 mediates the anti-inflammatory 
      properties of a subset of over-the-counter and prescription NSAIDs.
PG  - 1082-1095.e5
LID - S1074-7613(22)00186-8 [pii]
LID - 10.1016/j.immuni.2022.04.015 [doi]
AB  - 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.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Eisenstein, Anna
AU  - Eisenstein A
AD  - Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA.
FAU - Hilliard, Brandon K
AU  - Hilliard BK
AD  - Department of Internal Medicine and Immunobiology, Yale School of Medicine, New 
      Haven, CT 06520, USA.
FAU - Pope, Scott D
AU  - Pope SD
AD  - Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; 
      Howard Hughes Medical Institute, New Haven, CT, USA.
FAU - Zhang, Cuiling
AU  - Zhang C
AD  - Department of Internal Medicine and Immunobiology, Yale School of Medicine, New 
      Haven, CT 06520, USA.
FAU - Taskar, Pranali
AU  - Taskar P
AD  - NGM Biopharmaceuticals, South San Francisco, CA 94080, USA.
FAU - Waizman, Daniel A
AU  - Waizman DA
AD  - Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
FAU - Israni-Winger, Kavita
AU  - Israni-Winger K
AD  - Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
FAU - Tian, Hui
AU  - Tian H
AD  - NGM Biopharmaceuticals, South San Francisco, CA 94080, USA.
FAU - Luan, Harding H
AU  - Luan HH
AD  - NGM Biopharmaceuticals, South San Francisco, CA 94080, USA. Electronic address: 
      hluan@ngmbio.com.
FAU - Wang, Andrew
AU  - Wang A
AD  - Department of Internal Medicine and Immunobiology, Yale School of Medicine, New 
      Haven, CT 06520, USA. Electronic address: andrew.wang@yale.edu.
LA  - eng
GR  - K08 AI128745/AI/NIAID NIH HHS/United States
GR  - R01 AI162645/AI/NIAID NIH HHS/United States
GR  - T32 AR007016/AR/NIAMS NIH HHS/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220518
PL  - United States
TA  - Immunity
JT  - Immunity
JID - 9432918
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
SB  - IM
CIN - Immunity. 2022 Jun 14;55(6):973-975. PMID: 35704999
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology/therapeutic use
MH  - *Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - Mice
MH  - *NF-E2-Related Factor 2/genetics
MH  - Prescriptions
MH  - Prostaglandin-Endoperoxide Synthases
PMC - PMC9205175
MID - NIHMS1810438
OTO - NOTNLM
OT  - growth/differentiation factor 15
OT  - nonsteroidal anti-inflammatory drugs
OT  - nuclear factor erythroid 2-related factor 2
COIS- 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.
EDAT- 2022/05/20 06:00
MHDA- 2022/06/18 06:00
PMCR- 2023/06/14
CRDT- 2022/05/19 18:53
PHST- 2021/12/23 00:00 [received]
PHST- 2022/03/08 00:00 [revised]
PHST- 2022/04/21 00:00 [accepted]
PHST- 2022/05/20 06:00 [pubmed]
PHST- 2022/06/18 06:00 [medline]
PHST- 2022/05/19 18:53 [entrez]
PHST- 2023/06/14 00:00 [pmc-release]
AID - S1074-7613(22)00186-8 [pii]
AID - 10.1016/j.immuni.2022.04.015 [doi]
PST - ppublish
SO  - Immunity. 2022 Jun 14;55(6):1082-1095.e5. doi: 10.1016/j.immuni.2022.04.015. Epub 
      2022 May 18.