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

Mills, E. L. et al. (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature, 5556, pp. 113-117. (doi:10.1038/nature25986) (PMID:29590092)

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Abstract

The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood1,2,3. 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.

Item Type:Articles (Letter)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Hartley, Professor Richard
Authors: Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., Jedrychowski, M. P., Costa, A. S.H., Higgins, M., Hams, E., Szpyt, J., Runtsch, M. C., King, M. A., McGouran, J. F., Fischer, R., Kessler, B. M., McGettrick, A. F., Hughes, M. M., Carroll, R. G., Booty, L. M., Knatko, E. V., Meakin, P. J., Ashford, M. L.J., Modis, L. K., Brunori, G., Sévin, D. C., Fallon, P. G., Caldwell, S. T., Kunji, E. R.S., Chouchani, E. T., Frezza, C., Dinkova-Kostova, A. T., Hartley, R. C., Murphy, M. P., and O’Neill, L. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Chemistry
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:28 March 2018
Copyright Holders:Copyright © 2018 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature 556:113-117
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
710821'Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZCHEM - CHEMISTRY