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


  • Brain Behavior and Immunity


  • Brain Behav Immun 48: 205-221


  • 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 intracerebroventricular (5 mug) 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-1beta and TNF-alpha genes. Furthermore, LPS preconditioning resulted in an increase in the amount of repressive histone modification H3K9me2 in the IL-1beta promoter. ChIP and knock-down experiments showed that NF-kappaB subunit RelB was bound to the IL-1beta 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 four 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.