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

Ryan, D. G. et al. (2022) Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience, 25(2), 103827. (doi: 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.

• Item Type: Articles
• Additional Information: We thank Cancer Research UK (C20953/A18644) and the Wellcome Trust (105024/Z/14/Z) for funding.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hartley, Professor Richard
• Authors: Ryan, D. G., Knatko, E. V., Casey, A. M., Hukelmann, J. L., Dayalan Naidu, S., Brenes, A. J., Ekkunagul, T., Baker, C., Higgins, M., Tronci, L., Nikitopolou, E., Honda, T., Hartley, R. C., O’Neill, L. A.J., Frezza, C., Lamond, A. I., Abramov, A. Y., Arthur, J. S. C., Cantrell, D. A., Murphy, M. P., and Dinkova-Kostova, A. T.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: iScience
• Publisher: Elsevier (Cell Press)
• ISSN: 2589-0042
• Published Online: 30 January 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in iScience 25(2): 103827
• Publisher Policy: Reproduced under a Creative Commons licence