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Cell. 2018 Jan 11;172(1-2):135-146.e9. doi: 10.1016/j.cell.2017.11.025.

Metabolic Induction of Trained Immunity through the Mevalonate Pathway.

Author information

1
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
2
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
3
Faculty of Science, Department of Molecular Biology, Radboud University, 6525GA Nijmegen, the Netherlands.
4
Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
5
Department of Genetics, University Medical Center Groningen, Nijmegen, the Netherlands.
6
Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
7
Department of Medicine, Division of Endocrinology, Radboud University Nijmegen, Geert Grooteplein 8, Nijmegen, the Netherlands.
8
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Medical Genetics, University of Medicine and Pharmacy "Iuliu Hatieganu," Cluj-Napoca, Romania.
9
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: niels.riksen@radboudumc.nl.
10
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany. Electronic address: mihai.netea@radboudumc.nl.

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.

KEYWORDS:

HIDS; epigenetics; hyper IgD syndrome; immunometabolism; innate immune memory; macrophages; metabolism; mevalonate kinase deficiency; monocytes; trained immunity

PMID:
29328908
DOI:
10.1016/j.cell.2017.11.025
[Indexed for MEDLINE]
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