Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing
| Autor: | Bart J. L. Eggen, Sabrina Jacobs, Petya B. Georgieva, P. J. van den Elsen, Hendrikus Boddeke, Helmut Kettenmann, Wandert Schaafsma, Nieske Brouwer, Peter Meerlo, Susanne A. Wolf, Nasrin Saiepour, Uwe Karsten Hanisch, Xiaoming Zhang, K. C. van Zomeren, Hana Janova |
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| Přispěvatelé: | Pathology, NCA - Neuroinflamation, Meerlo lab, Molecular Neuroscience and Ageing Research (MOLAR), Translational Immunology Groningen (TRIGR), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE) |
| Rok vydání: | 2015 |
| Předmět: |
Lipopolysaccharides
Programmed cell death Immunology Interleukin-1beta Endotoxin tolerance Inflammation DISTINCT Biology Nitric oxide Epigenesis Genetic PHAGOCYTOSIS Histones Behavioral Neuroscience chemistry.chemical_compound Mice Epigenetic silencing CHROMATIN MODIFICATIONS medicine Animals Gene Silencing Promoter Regions Genetic IN-VIVO Innate immunity Innate immune system Microglia Endocrine and Autonomic Systems Tumor Necrosis Factor-alpha RELB Transcription Factor RelB HISTONE NF-kappa B COGNITIVE IMPAIRMENT Molecular biology TNF-ALPHA Cell biology medicine.anatomical_structure RECEPTOR ACTIVATION chemistry CELL-DEATH Tumor necrosis factor alpha medicine.symptom Chromatin immunoprecipitation |
| Zdroj: | Brain Behavior and Immunity, 48, 205-221. Academic Press Inc. Brain, Behavior, and Immunity, 48, 205-221 Brain, Behavior, and Immunity, 48, 205-221. ACADEMIC PRESS INC ELSEVIER SCIENCE 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 & Eggen, B J L 2015, ' Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing ', Brain Behavior and Immunity, vol. 48, pp. 205-221 . https://doi.org/10.1016/j.bbi.2015.03.013 |
| ISSN: | 0889-1591 |
| DOI: | 10.1016/j.bbi.2015.03.013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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