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Nrf2 is a central regulator of the metabolic landscape in macrophages and finetunes their inflammatory response

ABSTRACT: To overcome oxidative, inflammatory, and metabolic stress, cells have evolved networks of cytoprotective proteins controlled by transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator the Kelch-like ECH associated protein 1 (Keap1). Here, we used high-resolution mass-spectrometry to characterize the proteomes of macrophages with altered Nrf2 status. Our analysis revealed significant differences among the genotypes in cellular metabolism and redox homeostasis, which we validated with Seahorse flux and metabolomics, as well as in anti-viral immune pathways, translational regulation and mitosis. Nrf2 disruption significantly affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity predominantly. Of note, LPS stimulation was found to promote mitochondrial fusion in a process that was dependent on Nrf2. The Keap1 inhibitor, 4-octyl itaconate (4-OI), a derivative of the mitochondrial immunometabolite itaconate, remodeled the inflammatory macrophage proteome, increasing redox and suppressing anti-viral immune effectors in a Nrf2-dependent manner. These data suggest that Nrf2 activation facilitates metabolic reprogramming, mitochondrial adaptation, and finetunes the innate immune response in macrophages.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow Macrophage

SUBMITTER: Alejandro Brenes

LAB HEAD: Doreen A. Cantrell

PROVIDER: PXD027737 | Pride | 2021-08-13

REPOSITORIES: Pride

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