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

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

doi:10.1016/j.isci.2022.103827

Abstract

SummaryTo 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.

Highlights

The transcription factor (TF) nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, gene name Nfe2l2), and its negative regulator Kelch-like ECH associated protein 1 (Keap1) are at the interface of redox and intermediate metabolism (Hayes and Dinkova-Kostova, 2014; Yamamoto et al, 2018), and have a complex, but incompletely understood, function in infection, inflammation, and immunity (Cuadrado et al, 2020)
SUMMARY To overcome oxidative, inflammatory, and metabolic stress, cells have evolved cytoprotective protein networks controlled by nuclear factor-erythroid 2 p45related factor 2 (Nrf2) and its negative regulator, Kelch-like ECH associated protein 1 (Keap1)
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

Summary

Introduction

The transcription factor (TF) nuclear factor-erythroid 2 p45-related factor 2 (Nrf, gene name Nfe2l2), and its negative regulator Kelch-like ECH associated protein 1 (Keap1) are at the interface of redox and intermediate metabolism (Hayes and Dinkova-Kostova, 2014; Yamamoto et al, 2018), and have a complex, but incompletely understood, function in infection, inflammation, and immunity (Cuadrado et al, 2020). This is not surprising considering that infection and inflammation cause disturbances in cellular redox homeostasis, which is restored by the upregulation of Nrf2-target proteins (Hayes and Dinkova-Kostova, 2014). Nrf is inactivated by herpes simplex virus 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while the Nrf activators 4-octyl itaconate (4-OI), sulforaphane, 2-cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (Figure S1), and its C-28 methyl ester (CDDO-Me, bardoxolone methyl) inhibit the replication of these viruses, correlating with increased resistance to infection (Olagnier et al, 2020; Ordonez et al, 2021; Sun et al, 2021; Wyler et al, 2019)

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