Document Type
Article
Publication Date
12-13-2016
Description
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Citation Information
Arts, Rob J.W.; Novakovic, Boris; ter Horst, Rob; Carvalho, Agostinho; Bekkering, Siroon; Lachmandas, Ekta; Rodrigues, Fernando; Silvestre, Ricardo; Cheng, Shih Chin; Wang, Shuang Yin; Habibi, Ehsan; Gonçalves, Luís G.; Mesquita, Inês; Cunha, Cristina; van Laarhoven, Arjan; van de Veerdonk, Frank L.; Williams, David L.; van der Meer, Jos; Logie, Colin; O'Neill, Luke A.; Dinarello, Charles A.; Riksen, Niels P.; van Crevel, Reinout; Clish, Clary; Notebaart, Richard A.; Joosten, Leo A.B.; Stunnenberg, Hendrik G.; and Xavier, Ramnik J.. 2016. Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metabolism. Vol.24(6). 807-819. https://doi.org/10.1016/j.cmet.2016.10.008 PMID: 27866838 ISSN: 1550-4131
Copyright Statement
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).