| Literature DB >> 27866838 |
Rob J W Arts1, Boris Novakovic2, Rob Ter Horst3, Agostinho Carvalho4, Siroon Bekkering3, Ekta Lachmandas3, Fernando Rodrigues4, Ricardo Silvestre4, Shih-Chin Cheng5, Shuang-Yin Wang2, Ehsan Habibi2, Luís G Gonçalves6, Inês Mesquita4, Cristina Cunha4, Arjan van Laarhoven3, Frank L van de Veerdonk3, David L Williams7, Jos W M van der Meer3, Colin Logie2, Luke A O'Neill8, Charles A Dinarello9, Niels P Riksen3, Reinout van Crevel3, Clary Clish10, Richard A Notebaart3, Leo A B Joosten3, Hendrik G Stunnenberg2, Ramnik J Xavier11, Mihai G Netea3.
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.Entities:
Keywords: cholesterol metabolism; epigenetics; glutamine metabolism; glycolysis; trained immunity
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Year: 2016 PMID： 27866838 PMCID： PMC5742541 DOI： 10.1016/j.cmet.2016.10.008
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287