Format

Send to

Choose Destination
Nature. 2018 Apr;556(7702):501-504. doi: 10.1038/s41586-018-0052-z. Epub 2018 Apr 18.

Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
2
Computer Technologies Department, ITMO University, Saint Petersburg, Russia.
3
Agios Pharmaceuticals, Cambridge, MA, USA.
4
Division of Dermatology, Center for Pharmacogenomics, Center for the Study of Itch, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Chemistry, McGill University, Montreal, Quebec, Canada.
6
Department of Biological Sciences, Columbia University, New York, NY, USA.
7
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
8
Elucidata Corporation, Cambridge, MA, USA.
9
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
10
Host Defense, Immunology Frontier Research Center, Osaka University, Suita, Japan.
11
Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH, USA.
12
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. martyomov@wustl.edu.

Abstract

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.

PMID:
29670287
PMCID:
PMC6037913
DOI:
10.1038/s41586-018-0052-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center