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. 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

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)

Cell Signalling and Immunology

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63 Citations (Scopus)

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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.

Original language	English
Article number	103827
Number of pages	21
Journal	iScience
Volume	25
Issue number	2
Early online date	29 Jan 2022
DOIs	https://doi.org/10.1016/j.isci.2022.103827
Publication status	Published - 18 Feb 2022

Keywords

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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10.1016/j.isci.2022.103827Licence: CC BY

Final Published VersionFinal published version, 4.79 MBLicence: CC BY

Cite this

Ryan, D. G., Knatko, E. V., Casey, A. M., Hukelmann, J., 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., ... Dinkova-Kostova, A. T. (2022). Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience, 25(2), Article 103827. https://doi.org/10.1016/j.isci.2022.103827

@article{a6e189cba30a4734a03eea7563a3e2dc,

title = "Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response",

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 = "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",

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

note = "We thank Cancer Research UK (C20953/A18644) and the Wellcome Trust (105024/Z/14/Z) for funding",

year = "2022",

month = feb,

day = "18",

doi = "10.1016/j.isci.2022.103827",

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier",

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Ryan, DG, Knatko, EV, Casey, AM, Hukelmann, J, Dayalan Naidu, S , Brenes, AJ, Ekkunagul, T, Baker, C, Higgins, M, Tronci, L, Nikitopolou, E, Honda, T, Hartley, RC, O'Neill, LAJ, Frezza, C, Lamond, AI, Abramov, AY, Arthur, JSC , Cantrell, DA, Murphy, MP & Dinkova-Kostova, AT 2022, 'Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response', iScience, vol. 25, no. 2, 103827. https://doi.org/10.1016/j.isci.2022.103827

TY - JOUR

T1 - Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response

AU - Ryan, Dylan G.

AU - Knatko, Elena V.

AU - Casey, Alva M.

AU - Hukelmann, Jens

AU - Dayalan Naidu, Sharadha

AU - Brenes, Alejandro J.

AU - Ekkunagul, Thanapon

AU - Baker, Christa

AU - Higgins, Maureen

AU - Tronci, Laura

AU - Nikitopolou, Efterpi

AU - Honda, Tadashi

AU - Hartley, Richard C.

AU - O'Neill, Luke A. J.

AU - Frezza, Christian

AU - Lamond, Angus I.

AU - Abramov, Andrey Y.

AU - Arthur, J. Simon C.

AU - Cantrell, Doreen A.

AU - Murphy, Michael P.

AU - Dinkova-Kostova, Albena T.

N1 - We thank Cancer Research UK (C20953/A18644) and the Wellcome Trust (105024/Z/14/Z) for funding

PY - 2022/2/18

Y1 - 2022/2/18

N2 - 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.

AB - 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.

KW - Nrf2

KW - Nfe2/2

KW - Keap1

KW - LPS

KW - 4-octyl itaconate

KW - macrophage

KW - immunometabolism

KW - mitochondria

KW - mitochondrial dynamics

KW - innate immunity

KW - cytokine

KW - anti-viral immune response

KW - mass spectrometry

KW - proteomics

KW - Biochemistry

KW - Immunology

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=85124281946&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2022.103827

DO - 10.1016/j.isci.2022.103827

M3 - Article

C2 - 35198887

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 2

M1 - 103827

ER -

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

Abstract

Keywords

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The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)

Investigating the murine bone marrow derived macrophage response to Candida albicans infection

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)

Student theses

Investigating the murine bone marrow derived macrophage response to Candida albicans infection

Cite this