Wnt-3a exacerbates production of TNF-α in LPS stimulated microglia independent of the β-catenin canonical pathway.

Neuroinflammatory pathways are emerging therapeutic targets for neurological conditions such as Parkinson's disease (PD). Wnt-3a may exert anti-inflammatory effects via canonical pathway activation and β-catenin stabilization while dysregulation of the Wnt/β-catenin pathway has been implicated in the degeneration of dopamine neurons in PD. However, canonical pathway stimulation via application of Wnt-3a to protect against inflammation and dopaminergic degeneration has not been explored. We found Wnt-3a alone had no effect on pro-inflammatory TNF-α or IL-1β release from homeostatic primary microglia, however co-administration with LPS significantly increased TNF-α release beyond that seen with LPS alone. This exacerbation in TNF-α levels was not mediated by the NFκB pathway or activation of β-catenin. Canonical pathway inhibition via DKK1 showed no changes in TNF-α levels, however both SP600125 and U723122 were able to block Wnt-3a + LPS induced TNF-α release, implicating non-canonical pathways. Meanwhile, infusion of Wnt-3a in vivo did not alter dopaminergic or microglial populations in MPTP lesioned animals. Together, these findings suggest Wnt-3a may enhance pro-inflammatory TNF-α release via non-canonical signaling in inflammatory conditions, with minimal effect on homeostatic microglia. This demonstrates the importance of cellular context when identifying potential therapies for neurodegenerative diseases where neuroinflammation is a critical mediator of pathology.