Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response.
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Authors
Ryan, Dylan G
Knatko, Elena V
Casey, Alva M
Hukelmann, Jens L
Dayalan Naidu, Sharadha
Brenes, Alejandro J
Ekkunagul, Thanapon
Baker, Christa
Higgins, Maureen
Tronci, Laura
Nikitopolou, Efterpi
Honda, Tadashi
Hartley, Richard C
O'Neill, Luke AJ
Frezza, Christian
Lamond, Angus I
Abramov, Andrey Y
Arthur, J Simon C
Cantrell, Doreen A
Murphy, Michael P
Dinkova-Kostova, Albena T
Publication Date
2022-02-18Journal Title
iScience
ISSN
2589-0042
Publisher
Elsevier BV
Volume
25
Issue
2
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ryan, D. G., Knatko, E. V., Casey, A. M., Hukelmann, J. L., Dayalan Naidu, S., Brenes, A. J., Ekkunagul, T., et al. (2022). Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response.. iScience, 25 (2) https://doi.org/10.1016/j.isci.2022.103827
Abstract
To overcome oxidative, inflammatory, and metabolic stress, cells have evolved cytoprotective protein networks controlled by nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and its negative regulator, Kelch-like ECH associated protein 1 (Keap1). Here, using high-resolution mass spectrometry we characterize the proteomes of macrophages with altered Nrf2 status revealing significant differences among the genotypes in metabolism and redox homeostasis, which were validated with respirometry and metabolomics. Nrf2 affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity. Notably, Nrf2 activation promoted mitochondrial fusion. The Keap1 inhibitor, 4-octyl itaconate remodeled the inflammatory macrophage proteome, increasing redox and suppressing type I interferon (IFN) response. Similarly, pharmacologic or genetic Nrf2 activation inhibited the transcription of IFN-β and its downstream effector IFIT2 during LPS stimulation. These data suggest that Nrf2 activation facilitates metabolic reprogramming and mitochondrial adaptation, and finetunes the innate immune response in macrophages.
Keywords
Biochemistry, Proteomics, immunology
Sponsorship
MRC (MC_UU_00015/3)
Wellcome Trust (WELL-)
Medical Research Council (MC_UU_12022/6)
Medical Research Council (MC_UU_00015/3)
Identifiers
35198887, PMC8844662
External DOI: https://doi.org/10.1016/j.isci.2022.103827
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335427
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