Abstract:
BACKGROUND:Ischemic stroke is a leading cause of disability worldwide and characteristically accompanied by downregulation of the Wnt/β-catenin signaling. Activation of Wnt/β-catenin signaling emerges to attenuate neuroinflammation after ischemic stroke; however, its effect on modulating microglial polarization is largely unknown. Here, we explored whether Wnt/β-catenin pathway activator TWS119 facilitated long-term neurological recovery via modulating microglia polarization after experimental stroke. METHODS:Ischemic stroke mice model was induced by permanent distal middle cerebral artery occlusion plus 1 h hypoxia. TWS119 was administrated from day 1 to 14 after stroke. Neurological deficits were monitored up to 21 days after stroke. Angiogenesis, neural plasticity, microglial polarization, and microglia-associated inflammatory cytokines were detected in the peri-infarct cortex at days 14 and 21 after stroke. Primary microglia and mouse brain microvascular endothelial cell lines were employed to explore the underlying mechanism in vitro. RESULTS:TWS119 mitigated neurological deficits at days 14 and 21 after experimental stroke, paralleled by acceleration on angiogenesis and neural plasticity in the peri-infarct cortex. Mechanistically, cerebral ischemia induced production of microglia-associated proinflammatory cytokines and priming of activated microglia toward pro-inflammatory polarization, whereas TWS119 ameliorated microglia-mediated neuroinflammatory status following ischemic stroke and promoted angiogenesis by modulating microglia to anti-inflammatory phenotype. The beneficial efficacy of TWS119 in microglial polarization was largely reversed by selective Wnt/β-catenin pathway blockade in vitro, suggesting that TWS119-enabled pro-inflammatory to anti-inflammatory phenotype switch of microglia was possibly mediated by Wnt/β-catenin signaling. CONCLUSIONS:Wnt/β-catenin pathway activator TWS119 ameliorated neuroinflammatory microenvironment following chronic cerebral ischemia via modulating microglia towards anti-inflammatory phenotype, and facilitates neurological recovery in an anti-inflammatory phenotype polarization-dependent manner. Activation of Wnt/β-catenin pathway following ischemic stroke might be a potential restorative strategy targeting microglia-mediated neuroinflammation.
journal_name
J Neuroinflammationjournal_title
Journal of neuroinflammationauthors
Song D,Zhang X,Chen J,Liu X,Xue J,Zhang L,Lan Xdoi
10.1186/s12974-019-1660-8subject
Has Abstractpub_date
2019-12-06 00:00:00pages
256issue
1issn
1742-2094pii
10.1186/s12974-019-1660-8journal_volume
16pub_type
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