Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

Rob J.W. Arts*, Boris Novakovic, Rob ter Horst, Agostinho Carvalho, Siroon Bekkering, Ekta Lachmandas, Fernando Rodrigues, Ricardo Silvestre, Shih Chin Cheng, Shuang Yin Wang, Ehsan Habibi, Luís G. Gonçalves, Inês Mesquita, Cristina Cunha, Arjan van Laarhoven, Frank L. van de Veerdonk, David L. Williams, Jos W.M. van der Meer, Colin Logie, Luke A. O'NeillCharles A. Dinarello, Niels P. Riksen, Reinout van Crevel, Clary Clish, Richard A. Notebaart, Leo A.B. Joosten, Hendrik G. Stunnenberg, Ramnik J. Xavier, Mihai G. Netea

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

284 Citations (Scopus)

Abstract

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

Original languageEnglish
Pages (from-to)807-819
JournalCell Metabolism
Volume24
Issue number6
DOIs
Publication statusPublished - 13 Dec 2016
Externally publishedYes

Keywords

  • cholesterol metabolism
  • epigenetics
  • glutamine metabolism
  • glycolysis
  • trained immunity

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