1. Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
- Author
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Reinout van Crevel, Hendrik G. Stunnenberg, Boris Novakovic, David L. Williams, Charles A. Dinarello, Ekta Lachmandas, Fernando Rodrigues, Ricardo Silvestre, Inês Mesquita, Agostinho Carvalho, Richard A. Notebaart, Ehsan Habibi, Cristina Cunha, Shuang-Yin Wang, Jos W. M. van der Meer, Luís G. Gonçalves, Clary B. Clish, Siroon Bekkering, Colin Logie, Ramnik J. Xavier, Rob J.W. Arts, Arjan van Laarhoven, Luke A. J. O'Neill, Mihai G. Netea, Shih-Chin Cheng, Leo A. B. Joosten, Niels P. Riksen, Frank L. van de Veerdonk, Rob ter Horst, Habibi, Ehsan, and Universidade do Minho
- Subjects
0301 basic medicine ,Physiology ,Glutamine ,animal diseases ,Medicina Básica [Ciências Médicas] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Epigenesis, Genetic ,Pentose Phosphate Pathway ,trained immunity ,Fumarates ,glutamine metabolism ,Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] ,glycolysis ,3. Good health ,Cell biology ,Cholesterol ,medicine.anatomical_structure ,Ciências Médicas::Medicina Básica ,Epigenetics ,Reprogramming ,Glycolysis ,chemical and pharmacologic phenomena ,Trained immunity ,Biology ,Models, Biological ,Article ,03 medical and health sciences ,Immune system ,Immunity ,Immune Tolerance ,medicine ,Humans ,Cholesterol metabolism ,Molecular Biology ,Innate immune system ,Glutaminolysis ,Science & Technology ,epigenetics ,Macrophages ,Monocyte ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,Hypoxia-Inducible Factor 1, alpha Subunit ,Immunity, Innate ,Metabolic pathway ,Glucose ,030104 developmental biology ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Proteolysis ,Immunology ,cholesterol metabolism ,Glutamine metabolism ,bacteria - 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 ß-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 ß-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by ß-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., Netherlands Organization for Scientific Research (NWO). B.N. is supported by an NHMRC (Australia) CJ Martin Early Career Fellowship. N.P.R. Netherlands Heart Foundation (2012T051). N.P.R. and M.G.N. received a H2020 grant (H2020-PHC-2015-667873-2) from the European Union (grant agreement 667837). Fundação para a Ciência e Tecnologia, FCT (IF/00735/2014 to A.C., IF/00021/2014 to R.S., RECI/BBB-BQB/0230/2012 to L.G.G., and SFRH/BPD/96176/2013 to C. Cunha). The NMR spectrometers are part of the National NMR Facility supported by FCT (RECI/BBB-BQB/0230/2012). The research leading to these results received funding from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). NIH (DK43351 and DK097485) and Helmsley Trust. D.L.W. is supported, in part, by the NIH (GM53522, GM083016, GM119197, and C06RR0306551)
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