Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.

peer reviewedSince its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate

Author Correction: SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

An amendment to this paper has been published and can be accessed via a link at the top of the paper

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Versiones preprint disponibles en: http://hdl.handle.net/10261/216920 y http://hdl.handle.net/10261/217161Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.This research work was supported by Ester M og Konrad Kristian Sigurdssons Dyreværnsfond, Beckett-Fonden, Kong Christian IX og Dronning Louises Jubilæumslegat, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis´ legat, Købmand I Odense Johan og Hanne Weimann Født Seedorffs Legat, Hørslev Fonden, UK Medical Research Council (MRC core funding of the MRC Human Immunology Unit; JR), Lundbeck foundation (R303-2018-3379 and R219-2016-878, and R268-2016-3927), and Independent Research Fund Denmark – Medical Sciences (9039-00078B, 4004-00047B, and 0214-00001B). CarlsbergFoundation (Semper Ardens) and European Research Council (ERC-AdG ENVISION; 786602). Marie Skłodowska-Curie Action of the European Commission # 813343 and Italian Cancer Research Society #22891 to JH.Peer reviewe