Differential TGF-β signaling in glial subsets underlies IL-6-mediated epileptogenesis in mice

Nitzan Levy, Dan Z. Milikovsky, Gytis Baranauskas, Ekaterina Vinogradov, Yaron David, Maya Ketzef, Shai Abutbul, Itai Weissberg, Lyn Kamintsky, Ilya Fleidervish, Alon Friedman, Alon Monsonego

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-β signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6-treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-β1-induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte-neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.

Original languageEnglish
Pages (from-to)1713-1722
Number of pages10
JournalJournal of Immunology
Volume195
Issue number4
DOIs
StatePublished - 15 Aug 2015

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