TY - JOUR
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
N1 - Publisher Copyright:
© 2017 The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85030102941&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-00769-0
DO - 10.1038/s41467-017-00769-0
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 28959042
AN - SCOPUS:85030102941
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 717
ER -
