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Immunometabolic Pathways in BCG-Induced Trained Immunity

2016; Cell Press; Volume: 17; Issue: 10 Linguagem: Inglês

10.1016/j.celrep.2016.11.011

2639-1856

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

Epigenetics and DNA Methylation

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.