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

Dylan G Ryan; Elena V Knatko; Alva M Casey; Jens L 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 Murphy; Albena T Dinkova-Kostova

doi:10.1016/j.isci.2022.103827

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

iScience. 2022 Jan 30;25(2):103827. doi: 10.1016/j.isci.2022.103827. eCollection 2022 Feb 18.

Authors

Dylan G Ryan^{1

2}, Elena V Knatko³, Alva M Casey⁴, Jens L Hukelmann^{5

6}, Sharadha Dayalan Naidu³, Alejandro J Brenes^{5

6}, Thanapon Ekkunagul³, Christa Baker⁵, Maureen Higgins³, Laura Tronci², Efterpi Nikitopolou², Tadashi Honda⁷, Richard C Hartley⁸, Luke A J O'Neill¹, Christian Frezza², Angus I Lamond⁶, Andrey Y Abramov⁹, J Simon C Arthur⁵, Doreen A Cantrell⁵, Michael P Murphy⁴, Albena T Dinkova-Kostova^{3

10}

Affiliations

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
² Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK.
³ Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK.
⁴ Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
⁵ Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
⁶ Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
⁷ Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
⁸ School of Chemistry, University of Glasgow, Glasgow, UK.
⁹ Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
¹⁰ Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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; Immunology; Proteomics.

Abstract

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