Metabolic Induction of Trained Immunity through the Mevalonate Pathway

Siroon Bekkering, Rob J W Arts, Boris Novakovic, Ioannis Kourtzelis, Charlotte D C C van der Heijden, Yang Li, Calin D Popa, Rob Ter Horst, Julia van Tuijl, Romana T Netea-Maier, Frank L van de Veerdonk, Triantafyllos Chavakis, Leo A B Joosten, Jos W M van der Meer, Henk Stunnenberg, Niels P Riksen, Mihai G Netea

Research output: Contribution to journalArticlepeer-review

Abstract

Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.

Original languageEnglish
Pages (from-to)135-146
JournalCell
Volume172
Issue number1-2
DOIs
Publication statusPublished - 11 Jan 2018

Bibliographical note

Copyright © 2017 Elsevier Inc. All rights reserved.

Keywords

  • Animals
  • Cells, Cultured
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
  • Immunity, Innate
  • Immunologic Memory
  • Male
  • Mevalonate Kinase Deficiency/immunology
  • Mevalonic Acid/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Monocytes/drug effects
  • Receptor, IGF Type 1/metabolism

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