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Cell. 2016 Nov 17;167(5):1354-1368.e14. doi: 10.1016/j.cell.2016.09.034.

β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

Author information

1
Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
2
Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6525 GA Nijmegen, the Netherlands.
3
Department of Intensive Care Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases (RCI), 6500 HB Nijmegen, the Netherlands.
4
Department of Molecular Developmental Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
5
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
6
Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, 08028 Barcelona, Spain.
7
Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands. Electronic address: h.stunnenberg@ncmls.ru.nl.

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.

KEYWORDS:

BLUEPRINT; endotoxin tolerance; epigenome; histone modifications; human monocytes; lipopolysaccharide; macrophages; trained innate immunity; transcriptome; β-glucan

PMID:
27863248
PMCID:
PMC5927328
DOI:
10.1016/j.cell.2016.09.034
[Indexed for MEDLINE]
Free PMC Article

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