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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: |
Schaafsma, W., Zhang, X., van Zomeren, K.C., Jacobs, S., Georgieva, P.B.  ORCID: https://orcid.org/0000-0002-6347-2297, Wolf, S.A. ORCID: https://orcid.org/0000-0003-0922-8418, Kettenmann, H. ORCID: https://orcid.org/0000-0001-8208-0291, 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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