Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

Aleksandra Deczkowska; Orit Matcovitch-Natan; Afroditi Tsitsou-Kampeli; Sefi Ben-Hamo; Raz Dvir-Szternfeld; Amit Spinrad; Oded Singer; Eyal David; Deborah R. Winter; Lucas K. Smith; Alexander Kertser; Kuti Baruch; Neta Rosenzweig; Anna Terem; Marco Prinz; Saul Villeda; Ami Citri; Ido Amit; Michal Schwartz

doi:10.1038/s41467-017-00769-0

Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

Aleksandra Deczkowska, Orit Matcovitch-Natan, Afroditi Tsitsou-Kampeli, Sefi Ben-Hamo, Raz Dvir-Szternfeld, Amit Spinrad, Oded Singer, Eyal David, Deborah R. Winter, Lucas K. Smith, Alexander Kertser, Kuti Baruch, Neta Rosenzweig, Anna Terem, Marco Prinz, Saul Villeda, Ami Citri, Ido Amit^*, Michal Schwartz

^*Corresponding author for this work

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

166 Scopus citations

Abstract

During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-β in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.

Original language	English (US)
Article number	717
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00769-0
State	Published - Dec 1 2017

Funding

We thank Prof Steffen Jung for the kind gift of the Cx3cr1ERT2-Cre mice, Margalit Azulay for assistance with animal care, Prof Alon Chen, Raaya Zwang, and Maya Groysman for help with preparation of viruses for preliminary experiments, Dr Ofer Yizhar and his group for sharing stereotactic injection facilities, Dr Shelley Schwarzbaum for manuscript editing, and Tal Bigdary for artwork. Research in the M.S. lab is supported by Advanced European Research Council grants (232835), and by the EU Seventh Framework Program HEALTH-2011 (279017); Israel Science Foundation (ISF)-research grant no. 991/ 16, ISF-Legacy Heritage Biomedical Science Partnership-research grant no. 1354/15, and Consolidated Anti-Aging Foundation (CAFF). M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. Research in the I.A. lab is supported by the European Research Council (309788), the Israeli Science Foundation (1782/11), the BLUEPRINT FP7 consortium, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Minerva Stiftung research grant, the Israeli Ministry of Science, Technology and Space, the David and Fela Shapell Family Foundation, and the National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193). I.A. is the incumbent of the Alan and Laraine Fischer Career Development Chair. M.P. is supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the Sobek-Stiftung, the DFG (SFB 992, SFB1140, Reinhart-Koselleck-Grant), the ERA-Net NEURON initiative “NEURO-IFN” and the Sonderlinie Hochschulmedizin, project “neuroinflammation in neurodegeneration”. I.A. and M.P. are supported by the SFB/TRR167.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Deczkowska, A., Matcovitch-Natan, O., Tsitsou-Kampeli, A., Ben-Hamo, S., Dvir-Szternfeld, R., Spinrad, A., Singer, O., David, E., Winter, D. R., Smith, L. K., Kertser, A., Baruch, K., Rosenzweig, N., Terem, A., Prinz, M., Villeda, S., Citri, A., Amit, I., & Schwartz, M. (2017). Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner. Nature communications, 8(1), Article 717. https://doi.org/10.1038/s41467-017-00769-0

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title = "Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner",

abstract = "During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-β in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.",

author = "Aleksandra Deczkowska and Orit Matcovitch-Natan and Afroditi Tsitsou-Kampeli and Sefi Ben-Hamo and Raz Dvir-Szternfeld and Amit Spinrad and Oded Singer and Eyal David and Winter, {Deborah R.} and Smith, {Lucas K.} and Alexander Kertser and Kuti Baruch and Neta Rosenzweig and Anna Terem and Marco Prinz and Saul Villeda and Ami Citri and Ido Amit and Michal Schwartz",

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year = "2017",

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doi = "10.1038/s41467-017-00769-0",

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Deczkowska, A, Matcovitch-Natan, O, Tsitsou-Kampeli, A, Ben-Hamo, S, Dvir-Szternfeld, R, Spinrad, A, Singer, O, David, E, Winter, DR, Smith, LK, Kertser, A, Baruch, K, Rosenzweig, N, Terem, A, Prinz, M, Villeda, S, Citri, A, Amit, I & Schwartz, M 2017, 'Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner', Nature communications, vol. 8, no. 1, 717. https://doi.org/10.1038/s41467-017-00769-0

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T1 - Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

AU - Deczkowska, Aleksandra

AU - Matcovitch-Natan, Orit

AU - Tsitsou-Kampeli, Afroditi

AU - Ben-Hamo, Sefi

AU - Dvir-Szternfeld, Raz

AU - Spinrad, Amit

AU - Singer, Oded

AU - David, Eyal

AU - Winter, Deborah R.

AU - Smith, Lucas K.

AU - Kertser, Alexander

AU - Baruch, Kuti

AU - Rosenzweig, Neta

AU - Terem, Anna

AU - Prinz, Marco

AU - Villeda, Saul

AU - Citri, Ami

AU - Amit, Ido

AU - Schwartz, Michal

PY - 2017/12/1

Y1 - 2017/12/1

N2 - During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-β in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.

AB - During ageing, microglia acquire a phenotype that may negatively affect brain function. Here we show that ageing microglial phenotype is largely imposed by interferon type I (IFN-I) chronically present in aged brain milieu. Overexpression of IFN-β in the CNS of adult wild-type mice, but not of mice lacking IFN-I receptor on their microglia, induces an ageing-like transcriptional microglial signature, and impairs cognitive performance. Furthermore, we demonstrate that age-related IFN-I milieu downregulates microglial myocyte-specific enhancer factor 2C (Mef2C). Immune challenge in mice lacking Mef2C in microglia results in an exaggerated microglial response and has an adverse effect on mice behaviour. Overall, our data indicate that the chronic presence of IFN-I in the brain microenvironment, which negatively affects cognitive function, is mediated via modulation of microglial activity. These findings may shed new light on other neurological conditions characterized by elevated IFN-I signalling in the brain.

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Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

Abstract

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