Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response

Dylan G. Ryan, Elena V. Knatko, Alva M. Casey, Jens Hukelmann, Sharadha Dayalan Naidu, Alejandro J. Brenes, Thanapon Ekkunagul, Christa Baker, Maureen Higgins, Laura Tronci, Efterpi Nikitopolou, Tadashi Honda, Richard C. Hartley, Luke A. J. O'Neill, Christian Frezza, Angus I. Lamond, Andrey Y. Abramov, J. Simon C. Arthur, Doreen A. Cantrell, Michael P. MurphyAlbena T. Dinkova-Kostova (Lead / Corresponding author)

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54 Citations (Scopus)
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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.

Original languageEnglish
Article number103827
Number of pages21
Issue number2
Early online date29 Jan 2022
Publication statusPublished - 18 Feb 2022


  • Nrf2
  • Nfe2/2
  • Keap1
  • LPS
  • 4-octyl itaconate
  • macrophage
  • immunometabolism
  • mitochondria
  • mitochondrial dynamics
  • innate immunity
  • cytokine
  • anti-viral immune response
  • mass spectrometry
  • proteomics
  • Biochemistry
  • Immunology
  • Proteomics

ASJC Scopus subject areas

  • General


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