Immunometabolic Pathways in BCG-Induced Trained Immunity

Rob J W Arts, Agostinho Carvalho, Claudia La Rocca, Carla Palma, Fernando Eduardo Rodrigues Ferreira, Ricardo Silvestre, Johanneke Kleinnijenhuis, Ekta Lachmandas, Luis Pedro Goncalves, Ana Belinha, Cristina Cunha, Marije Oosting, Leo A B Joosten, Giuseppe Matarese, Reinout van Crevel, Mihai G. Netea

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation.

Original languageEnglish
Pages (from-to)2562-2571
Number of pages10
JournalCell Reports
Volume17
Issue number10
DOIs
Publication statusPublished - 6 Dec 2016

Keywords

  • BCG
  • epigenetics
  • glycolysis
  • immunometabolism
  • monocytes
  • trained immunity

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    Arts, R. J. W., Carvalho, A., La Rocca, C., Palma, C., Rodrigues Ferreira, F. E., Silvestre, R., ... Netea, M. G. (2016). Immunometabolic Pathways in BCG-Induced Trained Immunity. Cell Reports, 17(10), 2562-2571. https://doi.org/10.1016/j.celrep.2016.11.011