2. Academic Validation
  3. Dimethyl itaconate induces long-term innate immune responses and confers protection against infection

Dimethyl itaconate induces long-term innate immune responses and confers protection against infection

  • Cell Rep. 2023 Jun 27;42(6):112658. doi: 10.1016/j.celrep.2023.112658.
Anaísa V Ferreira 1,  Sarantos Kostidis 2,  Laszlo A Groh 3,  Valerie A C M Koeken 4,  Mariolina Bruno 3,  Ilayda Baydemir 3,  Gizem Kilic 3,  Özlem Bulut 3,  Theano Andriopoulou 5,  Victoria Spanou 5,  Kalliopi D Synodinou 5,  Theologia Gkavogianni 5,  Simone J C F M Moorlag 3,  L Charlotte de Bree 3,  Vera P Mourits 3,  Vasiliki Matzaraki 3,  Werner J H Koopman 6,  Frank L van de Veerdonk 3,  Georgios Renieris 5,  Martin Giera 2,  Evangelos J Giamarellos-Bourboulis 5,  Boris Novakovic 7,  Jorge Domínguez-Andrés 8
Affiliations

Affiliations

  • 1 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal. Electronic address: anaisa.validoferreira@radboudumc.nl.
  • 2 Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
  • 3 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands.
  • 4 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands; TWINCORE, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany; Centre for Individualised Infection Medicine (CiiM), Department of Computational Biology for Individualised Infection Medicine, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany.
  • 5 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
  • 6 Department of Pediatrics, Amalia Children's Hospital, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 7 Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
  • 8 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands. Electronic address: jorge.dominguezandres@radboudumc.nl.
PMID: 37330914 DOI: 10.1016/j.celrep.2023.112658
Abstract

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the Endogenous Metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to Infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context.

Keywords

CP: Immunology; glutathione; infection; innate immunity; itaconate; metabolism; monocytes; trained immunity.

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