Journal Article

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

O’Neill, Luke A., Meakin, Paul J., Hams, Emily, Fischer, Roman, Chouchani, Edward T., King, Martin S., Costa, Ana S. H., Ashford, Michael L. J., Murphy, Michael P., Mills, Evanna L., Higgins, Maureen, Booty, Lee M., Fallon, Padraic G., Szpyt, John, Dikovskaya, Dina, Frezza, Christian, Carroll, Richard G., Ryan, Dylan G., Knatko, Elena V., Dinkova-Kostova, Albena T., Menon, Deepthi, Brunori, Gino, Runtsch, Marah C., Jedrychowski, Mark P., Hughes, Mark M., Sévin, Daniel C., Hartley, Richard C., Kessler, Benedikt M., Modis, Louise K., Kunji, Edmund R. S., Prag, Hiran A., Zaslona, Zbigniew, McGouran, Joanna F., Caldwell, Stuart T., McGettrick, Anne F.

2018

Overview

WebTreatment of lipopolysaccharide-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-inflammatory transcription factor Nrf2 by alkylating key cysteine residues on the KEAP1 protein. Anti-inflammatory effects of itaconate Macrophages are white blood cells that recognize and destroy invading bacterial pathogens, and later tone down inflammation to enable tissue repair. The endogenous metabolite itaconate inhibits a number of inflammatory cytokines during macrophage activation. Luke O'Neill and colleagues investigate the mechanism underlying this process. Treatment of lipopolysaccharide (LPS)-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-oxidant and anti-inflammatory transcription factor Nrf2. This activation occurs via alkylation of key cysteine residues on the KEAP1 protein, which blocks KEAP1-dependent proteolysis of Nrf2. Pre-treating mouse models of LPS with the itaconate derivative activates Nrf2 and prolongs the survival of the animals after a lethal dose of LPS. The authors suggest that itaconate derivatives may prove useful in the treatment of inflammatory diseases. The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood 1 , 2 , 3 . Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1 ) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/21 / 13/31 / 38/77 / 38/89 / 631/250/2504/342 / 631/250/256/1980 / 631/45/320 / 64/60 / 82/1 / 82/58 / Activation analysis / Alkylates / Alkylation / Animals / Anti-Inflammatory Agents - metabolism / Anti-Inflammatory Agents - pharmacology / Carboxy-Lyases / Cattle / Cysteine / Cysteine - chemistry / Cysteine - metabolism / Cytokines / Cytokines - biosynthesis / Cytokines - immunology / Dehydrogenases / Enzymes / Feedback loops / Feedback, Physiological / Female / Gene expression / Genes / HEK293 Cells / Humanities and Social Sciences / Humans / Hydro-Lyases - biosynthesis / Inflammation / Interferon / Interferon-beta - immunology / Interferon-beta - pharmacology / Kelch-Like ECH-Associated Protein 1 - chemistry / Kelch-Like ECH-Associated Protein 1 - metabolism / Lethality / letter / Leucine zipper / Lipopolysaccharides / Lipopolysaccharides - immunology / Lipopolysaccharides - pharmacology / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Metabolites / Mice / multidisciplinary / Negative feedback / NF-E2-Related Factor 2 - agonists / NF-E2-Related Factor 2 - metabolism / Oxidizing agents / Physiological research / Proteins / Proteins - metabolism / Rats / Rats, Wistar / Residues / Rodents / Science / Sensors / Succinates - chemistry / Succinates - metabolism / Transcription activation