Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing

W. Schaafsma, X. Zhang, K. C. van Zomeren, S. Jacobs, P. B. Georgieva, S. A. Wolf, H. Kettenmann, H. Janova, N. Saiepour, U. -K. Hanisch, P. Meerlo, P. J. van den Elsen, N. Brouwer, H. W. G. M. Boddeke, B. J. L. Eggen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

58 Citations (Scopus)

Abstract

Microglia, the innate immune cells of the central nervous system (CNS), react to endotoxins like bacterial lipopolysaccharides (LPS) with a pronounced inflammatory response. To avoid excess damage to the CNS, the microglia inflammatory response needs to be tightly regulated. Here we report that a single LPS challenge results in a prolonged blunted pro-inflammatory response to a subsequent LPS stimulation, both in primary microglia cultures (100 ng/ml) and in vivo after intraperitoneal (0.25 and 1 mg/kg) or intracere-broventricular (5 mu g) LPS administration. Chromatin immunoprecipitation (ChIP) experiments with primary microglia and microglia acutely isolated from mice showed that LPS preconditioning was accompanied by a reduction in active histone modifications AcH3 and H3K4me3 in the promoters of the IL-10 and TNF-alpha genes. Furthermore, LPS preconditioning resulted in an increase in the amount of repressive histone modification H3K9me2 in the IL-1 beta promoter. ChIP and knock-down experiments showed that NF-kappa B subunit RelB was bound to the IL-1 beta promoter in preconditioned microglia and that RelB is required for the attenuated LPS response. In addition to a suppressed pro-inflammatory response, preconditioned primary microglia displayed enhanced phagocytic activity, increased outward potassium currents and nitric oxide production in response to a second LPS challenge. In vivo, a single i.p. LPS injection resulted in reduced performance in a spatial learning task 4 weeks later, indicating that a single inflammatory episode affected memory formation in these mice. Summarizing, we show that LPS-preconditioned microglia acquire an epigenetically regulated, immune-suppressed phenotype, possibly to prevent excessive damage to the central nervous system in case of recurrent (peripheral) inflammation. (C) 2015 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)205-221
Number of pages17
JournalBrain, Behavior, and Immunity
Volume48
DOIs
Publication statusPublished - Aug-2015

Keywords

  • Microglia
  • Innate immunity
  • Endotoxin tolerance
  • Epigenetic silencing
  • ENDOTOXIN TOLERANCE
  • CHROMATIN MODIFICATIONS
  • COGNITIVE IMPAIRMENT
  • RECEPTOR ACTIVATION
  • CELL-DEATH
  • TNF-ALPHA
  • IN-VIVO
  • HISTONE
  • DISTINCT
  • PHAGOCYTOSIS

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