Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response
Citation:
Ryan, D.G. and Knatko, E.V. and Casey, A.M. and Hukelmann, J.L. and Dayalan Naidu, S. and Brenes, A.J. and Ekkunagul, T. and Baker, C. and Higgins, M. and Tronci, L. and Nikitopolou, E. and Honda, T. and Hartley, R.C. and O'Neill, L.A.J. and Frezza, C. and Lamond, A.I. and Abramov, A.Y. and Arthur, J.S.C. and Cantrell, D.A. and Murphy, M.P. and Dinkova-Kostova, A.T., Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response, iScience, 25, 2, 2022Download Item:
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.
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http://people.tcd.ie/laoneill
Author: O'Neill, Luke
Type of material:
Journal ArticleCollections
Series/Report no:
iScience;25;
2;
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Full text availableKeywords:
cytoprotective protein networks, Kelch-like ECH associated protein 1 (Keap1), nuclear factor-erythroid 2 p45- related factor 2 (Nrf2), Biochemistry, Immunology, ProteomicsDOI:
http://dx.doi.org/10.1016/j.isci.2022.103827Metadata
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