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

Boris Novakovic, Ehsan Habibi, Shuang Yin Wang, Rob J.W. Arts, Robab Davar, Wout Megchelenbrink, Bowon Kim, Tatyana Kuznetsova, Matthijs Kox, Jelle Zwaag, Filomena Matarese, Simon J. van Heeringen, Eva M. Janssen-Megens, Nilofar Sharifi, Cheng Wang, Farid Keramati, Vivien Schoonenberg, Paul Flicek, Laura Clarke, Peter PickkersSimon Heath, Ivo Gut, Mihai G. Netea, Joost H.A. Martens, Colin Logie, Hendrik G. Stunnenberg

Research output: Contribution to journalArticlepeer-review

399 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1354-1368.e14
JournalCell
Volume167
Issue number5
DOIs
Publication statusPublished - 17 Nov 2016
Externally publishedYes

Keywords

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

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