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bioRxiv · 10.1101/2025.06.30.662485

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

Federici, G.·Stayte, S.·Rentsch, P.·Vissel, B.
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Abstract

BackgroundNeuroinflammatory pathways are emerging therapeutic targets for neurological conditions such as Parkinsons disease (PD). Studies have indicated Wnt-3a, a member of the wingless type MMTV integration (Wnt) signalling cascade, may exert anti-inflammatory effects via canonical pathway activation and {beta}-catenin stabilisation. Furthermore, dysregulation of the Wnt/{beta}-catenin pathway has been implicated in the degeneration of dopamine neurons in PD, however, stimulation of the canonical pathway via application of Wnt-3a to protect against inflammation and dopaminergic degeneration has not been explored. MethodsPrimary microglial cultures were stimulated with lipopolysaccharide (LPS) for 24 hours with or without Wnt-3a. TNF- levels were measured via ELISA while changes in NFkB inflammatory pathway proteins and phosphorylated and non-phosphorylated {beta}-catenin were analysed via capillary western blot. To assess Wnt pathway involvement, cultures were treated with DKK1 ({beta}-catenin canonical pathway inhibitor), SP600125 (Wnt/Pcp pathway inhibitor) or U73122 (Wnt/Ca2+ pathway inhibitor). Finally, C57BL/6 mice received continuous intracerebroventricular infusion of Wnt-3a via osmotic pumps to investigate the effects of Wnt-3a on dopaminergic neuron survival and on microglial numbers in the MPTP model of PD. ResultsWnt-3a alone had no effect on TNF- release from microglia. However, when co-administered with LPS, there was a significant increase in cytokine release beyond that seen with LPS alone. Protein analysis revealed that this exacerbation in TNF- levels was not due to alterations in the NFkB pathway or differences in activation of {beta}-catenin. Furthermore, DKK1 treated cells showed no changes in TNF- levels, however both SP600125 and U723122 were able to block Wnt-3a + LPS induced TNF- release, implicating the non-canonical pathways. Meanwhile Wnt-3a in vivo did not alter dopaminergic or microglial populations in the substantia nigra in MPTP lesioned animals. ConclusionTogether, these results suggest a pro-inflammatory response to Wnt-3a in an inflammatory context with little or no effect on resting microglia. Importantly, this outcome was independent of the {beta}-catenin canonical pathway, revealing that Wnt-3a can increase pro-inflammatory TNF- release via non-canonical signaling in an inflammatory environment. This demonstrates the importance of cellular context when identifying potential therapies for neurodegenerative diseases where neuroinflammation is a critical mediator of pathology.

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Federici, G., Stayte, S., Rentsch, P., Vissel, B.. 2025-07-04. Wnt-3a exacerbates production of TNF-α in LPS stimulated microglia independent of the β-catenin canonical pathway. https://doi.org/10.1101/2025.06.30.662485

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