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
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.
