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

Autor: Mills EL; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.; GlaxoSmithKline, Gunnelswood Road, Stevenage, Hertfordshire, UK., Ryan DG; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Prag HA; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK., Dikovskaya D; Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK., Menon D; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Zaslona Z; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Jedrychowski MP; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA., Costa ASH; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK., Higgins M; Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK., Hams E; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Szpyt J; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA., Runtsch MC; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., King MS; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK., McGouran JF; School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Fischer R; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK., Kessler BM; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK., McGettrick AF; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Hughes MM; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Carroll RG; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.; GlaxoSmithKline, Gunnelswood Road, Stevenage, Hertfordshire, UK., Booty LM; GlaxoSmithKline, Gunnelswood Road, Stevenage, Hertfordshire, UK.; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK., Knatko EV; Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK., Meakin PJ; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK., Ashford MLJ; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK., Modis LK; GlaxoSmithKline, Gunnelswood Road, Stevenage, Hertfordshire, UK., Brunori G; GlaxoSmithKline, Park Road, Ware, Hertfordshire, UK., Sévin DC; Cellzome, GlaxoSmithKline R&D, Heidelberg, Germany., Fallon PG; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Caldwell ST; WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK., Kunji ERS; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK., Chouchani ET; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA., Frezza C; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK., Dinkova-Kostova AT; Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA., Hartley RC; WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK., O'Neill LA; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.; GlaxoSmithKline, Gunnelswood Road, Stevenage, Hertfordshire, UK.
Jazyk: angličtina
Zdroj: Nature [Nature] 2018 Apr 05; Vol. 556 (7699), pp. 113-117. Date of Electronic Publication: 2018 Mar 28.
DOI: 10.1038/nature25986
Abstrakt: The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. 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.
Databáze: MEDLINE
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