Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke

Degang Song,Xifa Lan,Xiangjian Zhang,Junmin Chen,Lan Zhang,Xiaoxia Liu,Jing Xue

doi:10.1186/s12974-019-1660-8

Abstract

BackgroundIschemic 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.MethodsIschemic 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.ResultsTWS119 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.ConclusionsWnt/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.

Highlights

Ischemic stroke is a leading cause of disability worldwide and characteristically accompanied by downregulation of the Wnt/β-catenin signaling
TWS119-treated mice performed better in swing speed (41.86 ± 1.90 versus 58.80 ± 2.92 cm/s, P < 0.001; 44.93 ± 2.86 versus 69.90 ± 2.42 cm/s, P < 0.001, Fig. 2a), stride length (5.02 ± 0.13 versus 5.65 ± 0.12 cm, P < 0.01; 5.10 ± 0.13 versus 5.98 ± 0.11 cm, P < 0.001, Fig. 2b) and paw intensity (64.56 ± 2.17 versus 73.82 ± 1.70, P < 0.01; 70.21 ± 1.46 versus 79.13 ± 2.13, P < 0.01, Fig. 2c) of the left front limb compared with vehicle mice at days 14 and 21 after stroke, suggesting an improvement in gait performance attributed to TWS119 treatment
The present study demonstrated that the Wnt canonical pathway activator TWS119 exhibits significant efficacy in the improvement of neurological function following experimental stroke, paralleled by an acceleration of angiogenesis and neural plasticity in the peri-infarct cortex

Summary

Introduction

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; its effect on modulating microglial polarization is largely unknown. We explored whether Wnt/β-catenin pathway activator TWS119 facilitated long-term neurological recovery via modulating microglia polarization after experimental stroke. In response to cerebral ischemia, the brain initiates self-repair mechanisms and undergoes a post-stroke neurorestorative process. Angiogenesis and neural plasticity are major post-stroke neurorestorative elements. Extensive rewiring of remaining neuronal connections during the neural plasticity process leads to post-stroke cortical map rearrangement and functional improvement [4]. Seeking promising strategies on facilitating post-stroke angiogenesis and neural plasticity is paramount for long-term functional improvement

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Discussion

Conclusion