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

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Item Type:	Article
Title:	Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing
Creators Name:	Schaafsma, W., Zhang, X., van Zomeren, K.C., Jacobs, S., Georgieva, P.B., Wolf, S.A., Kettenmann, H., Janova, H., Saiepour, N., Hanisch, U.K., Meerlo, P., van den Elsen, P.J., Brouwer, N., Boddeke, H.W.G.M. and Eggen, B.J.L.
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 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.
Keywords:	Microglia, Innate Immunity, Endotoxin Tolerance, Epigenetic Silencing, Animals, Mice
Source:	Brain Behavior and Immunity
ISSN:	0889-1591
Publisher:	Elsevier / Academic Press
Volume:	48
Page Range:	205-221
Date:	August 2015
Official Publication:	https://doi.org/10.1016/j.bbi.2015.03.013
PubMed:	View item in PubMed

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