Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke
Background: Ischemic stroke is a leading cause of disability worldwide and is typically associated with the downregulation of the Wnt/β-catenin signaling pathway. Activating Wnt/β-catenin signaling has been shown to reduce neuroinflammation after ischemic stroke; however, its impact on microglial polarization remains largely unexplored. This study investigates whether the Wnt/β-catenin pathway activator, TWS119, promotes long-term neurological recovery by modulating microglial polarization after experimental stroke.
Methods: An ischemic stroke mouse model was induced using permanent distal middle cerebral artery occlusion combined with 1 hour of hypoxia. TWS119 was administered from day 1 to day 14 after stroke, and neurological deficits were monitored for up to 21 days. Angiogenesis, neural plasticity, microglial polarization, and levels of microglia-associated inflammatory cytokines were assessed in the peri-infarct cortex at days 14 and 21 post-stroke. Primary microglia and mouse brain microvascular endothelial cell lines were used to investigate the underlying mechanisms in vitro.
Results: TWS119 significantly improved neurological function at days 14 and 21 after experimental stroke, accompanied by enhanced angiogenesis and neural plasticity in the peri-infarct cortex. Mechanistically, ischemic stroke led to an increase in pro-inflammatory cytokines and activation of microglia toward a pro-inflammatory state. Treatment with TWS119 reduced neuroinflammation and promoted angiogenesis by shifting microglia towards an anti-inflammatory phenotype. The beneficial effects of TWS119 on microglial polarization were largely reversed by selective blockade of the Wnt/β-catenin pathway in vitro, indicating that the shift from pro-inflammatory to anti-inflammatory microglia was likely mediated by Wnt/β-catenin signaling.
Conclusions: The Wnt/β-catenin pathway activator TWS119 alleviates the neuroinflammatory microenvironment following chronic cerebral ischemia by modulating microglia toward an anti-inflammatory phenotype, thereby promoting neurological recovery in a polarization-dependent manner. These findings suggest that activation of the Wnt/β-catenin pathway may offer a potential therapeutic strategy for targeting microglia-mediated neuroinflammation after ischemic stroke.