title: Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity.
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.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: rob.jw.arts@radboudumc.nl.
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Arts
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 HP Nijmegen, the Netherlands.
authors.forename: Boris
authors.initials: B
authors.lastname: Novakovic
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ter Horst
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal.
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Siroon
authors.initials: S
authors.lastname: Bekkering
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Ekta
authors.initials: E
authors.lastname: Lachmandas
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Silvestre
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Institute of Molecular Medicine, National Tsing Hua University, 300 Hsinchu City, Taiwan.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 HP Nijmegen, the Netherlands.
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 HP Nijmegen, the Netherlands.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Habibi
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
authors.forename: Luís G
authors.initials: LG
authors.lastname: Gonçalves
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Mesquita
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: van Laarhoven
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Surgery, Quillen College of Medicine and Center for Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN 37604, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 HP Nijmegen, the Netherlands.
authors.forename: Colin
authors.initials: C
authors.lastname: Logie
authors.affiliation: Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Luke A
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Clary
authors.initials: C
authors.lastname: Clish
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Notebaart
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 HP Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D002784:Cholesterol / Q000378:metabolism; D044127:Epigenesis, Genetic; D005650:Fumarates / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008954:Models, Biological; D010427:Pentose Phosphate Pathway / Q000235:genetics; D059748:Proteolysis
chemical_list: D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005973:Glutamine; D002784:Cholesterol; D005947:Glucose
keywords: cholesterol metabolism; epigenetics; glutamine metabolism; glycolysis; trained immunity