title: β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.
abstract: Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, β-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo β-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT.
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Boris
authors.initials: B
authors.lastname: Novakovic
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Habibi
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6525 GA Nijmegen, the Netherlands.
authors.forename: Rob J W
authors.initials: RJW
authors.lastname: Arts
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Robab
authors.initials: R
authors.lastname: Davar
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Wout
authors.initials: W
authors.lastname: Megchelenbrink
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Bowon
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6500 HB Nijmegen, the Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6500 HB Nijmegen, the Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Zwaag
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: van Heeringen
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Janssen-Megens
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Farid
authors.initials: F
authors.lastname: Keramati
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Vivien
authors.initials: V
authors.lastname: Schoonenberg
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6500 HB Nijmegen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6525 GA Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Joost H A
authors.initials: JHA
authors.lastname: Martens
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
authors.forename: Colin
authors.initials: C
authors.lastname: Logie
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands. Electronic address: h.stunnenberg@ncmls.ru.nl.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
mesh_terms: D002454:Cell Differentiation; D019175:DNA Methylation; D057890:Epigenomics; D053263:Gene Regulatory Networks; D042421:Histone Code; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D007156:Immunologic Memory; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic; D047071:beta-Glucans / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D047071:beta-Glucans
keywords: BLUEPRINT; endotoxin tolerance; epigenome; histone modifications; human monocytes; lipopolysaccharide; macrophages; trained innate immunity; transcriptome; β-glucan