Creator(s)

Rob J.W. Arts, Radboud University Nijmegen Medical Centre
Boris Novakovic, Radboud University Nijmegen
Rob ter Horst, Radboud University Nijmegen Medical Centre
Agostinho Carvalho, Universidade do Minho, Escola de Ciências da Saúde
Siroon Bekkering, Radboud University Nijmegen Medical Centre
Ekta Lachmandas, Radboud University Nijmegen Medical Centre
Fernando Rodrigues, Universidade do Minho, Escola de Ciências da Saúde
Ricardo Silvestre, Universidade do Minho, Escola de Ciências da Saúde
Shih Chin Cheng, Radboud University Nijmegen Medical Centre
Shuang Yin Wang, Radboud University Nijmegen
Ehsan Habibi, Radboud University Nijmegen
Luís G. Gonçalves, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa
Inês Mesquita, Universidade do Minho, Escola de Ciências da Saúde
Cristina Cunha, Universidade do Minho, Escola de Ciências da Saúde
Arjan van Laarhoven, Radboud University Nijmegen Medical Centre
Frank L. van de Veerdonk, Radboud University Nijmegen Medical Centre
David L. Williams, East Tennessee State UniversityFollow
Jos van der Meer, Radboud University Nijmegen Medical Centre
Colin Logie, Radboud University Nijmegen
Luke A. O'Neill, Trinity College Dublin
Charles A. Dinarello, Radboud University Nijmegen Medical Centre
Niels P. Riksen, Radboud University Nijmegen Medical Centre
Reinout van Crevel, Radboud University Nijmegen Medical Centre
Clary Clish, Massachusetts Institute of Technology
Richard A. Notebaart, Radboud University Nijmegen Medical Centre
Leo A.B. Joosten, Radboud University Nijmegen Medical Centre
Hendrik G. Stunnenberg, Radboud University Nijmegen
Ramnik J. Xavier, Massachusetts Institute of Technology

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.

Copyright Statement

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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