Abstract
To overcome oxidative, inflammatory, and metabolic stress, cells have evolved networks of cytoprotective proteins controlled by 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 genetically altered Nrf2 status. Our analysis revealed significant differences among the genotypes in cellular metabolism and redox homeostasis, which we validated with respirometry and metabolomics, as well as in anti-viral immune pathways and the cell cycle. Nrf2 status significantly affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity observed. Of note, Nrf2 activation was found to promote mitochondrial fusion in inflammatory macrophages. 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 and mitochondrial adaptation, and finetunes the innate immune response in macrophages.
Highlights
First high-resolution proteome of macrophages with genetically altered Nrf2 status
Nrf2 is key regulator of macrophage redox and intermediary metabolism
Nrf2 finetunes the inflammatory response suppressing anti-viral immune and cytokine effectors, whilst promoting T cell activation factors
Nrf2 regulates mitochondrial adaptation in inflammatory macrophages promoting the formation of a fused network
4-octyl itaconate (4-OI) suppresses anti-viral immune effectors in inflammatory macrophages in a Nrf2-dependent manner
Competing Interest Statement
The authors have declared no competing interest.