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

iScience (Feb 2022)

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

Affiliations

Dylan G. Ryan: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
Elena V. Knatko: Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
Alva M. Casey: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
Jens L. Hukelmann: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK; Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
Sharadha Dayalan Naidu: Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
Alejandro J. Brenes: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK; Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
Thanapon Ekkunagul: Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
Christa Baker: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
Maureen Higgins: Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK
Laura Tronci: Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
Efterpi Nikitopolou: Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
Tadashi Honda: Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, USA
Richard C. Hartley: School of Chemistry, University of Glasgow, Glasgow, UK
Luke A.J. O’Neill: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
Christian Frezza: Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
Angus I. Lamond: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
Andrey Y. Abramov: Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK
J. Simon C. Arthur: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
Doreen A. Cantrell: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK
Michael P. Murphy: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
Albena T. Dinkova-Kostova: Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrott Drive, Dundee, Scotland, UK; Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author

Journal volume & issue: Vol. 25, no. 2
p. 103827

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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