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Wnt-3a exacerbates production of TNF-α in LPS stimulated microglia independent of the β-catenin canonical pathway
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  • Published: 11 February 2026

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

  • Gabrielle Federici1,
  • Sandy Stayte2,
  • Peggy Rentsch2,3 &
  • …
  • Bryce Vissel2,3 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Diseases
  • Neurology
  • Neuroscience

Abstract

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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Halleskog, C. et al. WNT signaling in activated microglia is Proinflammatory. Glia 59, 119–131. https://doi.org/10.1002/glia.21081 (2011).

    Google Scholar 

  2. Marchetti, B. & Pluchino, S. Wnt your brain be inflamed? Yes, it Wnt! Trends Mol. Med. 19, 144–156. https://doi.org/10.1016/j.molmed.2012.12.001 (2013).

    Google Scholar 

  3. Onyido, E. K., Sweeney, E. & Nateri, A. S. Wnt-signalling pathways and MicroRNAs network in carcinogenesis: experimental and bioinformatics approaches. Mol. Cancer. 15, 56. https://doi.org/10.1186/s12943-016-0541-3 (2016).

    Google Scholar 

  4. Clapham, D. E. Calcium signaling. Cell 131, 1047–1058. https://doi.org/10.1016/j.cell.2007.11.028 (2007).

    Google Scholar 

  5. Komiya, Y. & Habas, R. Wnt signal transduction pathways. Organogenesis 4, 68–75. https://doi.org/10.4161/org.4.2.5851 (2008).

    Google Scholar 

  6. Wei, L. et al. Activation of Wnt/beta-catenin pathway by exogenous Wnt1 protects SH-SY5Y cells against 6-hydroxydopamine toxicity. J. Mol. Neurosci. 49, 105–115. https://doi.org/10.1007/s12031-012-9900-8 (2013).

    Google Scholar 

  7. Castelo-Branco, G. et al. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc. Natl. Acad. Sci. U S A. 100, 12747–12752. https://doi.org/10.1073/pnas.1534900100 (2003).

    Google Scholar 

  8. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452. https://doi.org/10.1038/nature01611 (2003).

    Google Scholar 

  9. L’Episcopo, F. et al. Reactive astrocytes and Wnt/beta-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinson’s disease. Neurobiol. Dis. 41, 508–527. https://doi.org/10.1016/j.nbd.2010.10.023 (2011).

    Google Scholar 

  10. Verheyen, E. M. & Gottardi, C. J. Regulation of Wnt/beta-catenin signaling by protein kinases. Dev. Dyn. 239, 34–44. https://doi.org/10.1002/dvdy.22019 (2010).

    Google Scholar 

  11. Dun, Y. et al. Inhibition of the canonical Wnt pathway by Dickkopf-1 contributes to the neurodegeneration in 6-OHDA-lesioned rats. Neurosci. Lett. 525, 83–88. https://doi.org/10.1016/j.neulet.2012.07.030 (2012).

    Google Scholar 

  12. L’Episcopo, F. et al. A Wnt1 regulated Frizzled-1/beta-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol. Neurodegener. 6, 49. https://doi.org/10.1186/1750-1326-6-49 (2011).

    Google Scholar 

  13. Zhang, L. et al. Enhancing Beta-Catenin activity via GSK3beta Inhibition protects PC12 cells against rotenone toxicity through Nurr1 induction. PLoS One. 11, e0152931. https://doi.org/10.1371/journal.pone.0152931 (2016).

    Google Scholar 

  14. McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia Nigra of parkinson’s and alzheimer’s disease brains. Neurology 38, 1285–1291. https://doi.org/10.1212/wnl.38.8.1285 (1988).

    Google Scholar 

  15. Stefanova, N. Microglia in parkinson’s disease. J. Parkinsons Dis. 12, S105–S112. https://doi.org/10.3233/JPD-223237 (2022).

    Google Scholar 

  16. Lai, T. Microglial Inhibition alleviates alpha-synuclein propagation and neurodegeneration in parkinson’s disease mouse model. NPJ Parkinsons Dis. 10, 32. https://doi.org/10.1038/s41531-024-00640-2 (2024).

    Google Scholar 

  17. Liu, Q. et al. Single-cell sequencing of the substantia Nigra reveals microglial activation in a model of MPTP. Front. Aging Neurosci. 16, 1390310. https://doi.org/10.3389/fnagi.2024.1390310 (2024).

    Google Scholar 

  18. Lofrumento, D. D. et al. MPTP-induced neuroinflammation increases the expression of pro-inflammatory cytokines and their receptors in mouse brain. Neuroimmunomodulation 18, 79–88. https://doi.org/10.1159/000320027 (2011).

    Google Scholar 

  19. Stayte, S. et al. Activin A inhibits MPTP and LPS-Induced increases in inflammatory cell populations and loss of dopamine neurons in the mouse midbrain in vivo. PLoS One. 12, e0167211. https://doi.org/10.1371/journal.pone.0167211 (2017).

    Google Scholar 

  20. Collins, L. M., Toulouse, A., Connor, T. J. & Nolan, Y. M. Contributions of central and systemic inflammation to the pathophysiology of parkinson’s disease. Neuropharmacology 62, 2154–2168. https://doi.org/10.1016/j.neuropharm.2012.01.028 (2012).

    Google Scholar 

  21. Stephenson, J., Nutma, E., van der Valk, P. & Amor, S. Inflammation in CNS neurodegenerative diseases. Immunology 154, 204–219. https://doi.org/10.1111/imm.12922 (2018).

    Google Scholar 

  22. Yang, Y. & Zhang, Z. Microglia and Wnt pathways: prospects for inflammation in alzheimer’s disease. Front. Aging Neurosci. 12, 110. https://doi.org/10.3389/fnagi.2020.00110 (2020).

    Google Scholar 

  23. Gollamudi, S. et al. Concordant signaling pathways produced by pesticide exposure in mice correspond to pathways identified in human parkinson’s disease. PLoS One. 7, e36191. https://doi.org/10.1371/journal.pone.0036191 (2012).

    Google Scholar 

  24. Kwok, J. B. et al. GSK3B polymorphisms alter transcription and splicing in parkinson’s disease. Ann. Neurol. 58, 829–839. https://doi.org/10.1002/ana.20691 (2005).

    Google Scholar 

  25. L’Episcopo, F. et al. Wnt/beta-catenin signaling is required to rescue midbrain dopaminergic progenitors and promote neurorepair in ageing mouse model of parkinson’s disease. Stem Cells. 32, 2147–2163. https://doi.org/10.1002/stem.1708 (2014).

    Google Scholar 

  26. Ohnuki, T., Nakamura, A., Okuyama, S. & Nakamura, S. Gene expression profiling in progressively MPTP-lesioned macaques reveals molecular pathways associated with sporadic parkinson’s disease. Brain Res. 1346, 26–42. https://doi.org/10.1016/j.brainres.2010.05.066 (2010).

    Google Scholar 

  27. Zhang, L. et al. Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease. J. Genet. Genomics. 43, 587–592. https://doi.org/10.1016/j.jgg.2016.05.002 (2016).

    Google Scholar 

  28. Manicassamy, S. et al. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853. https://doi.org/10.1126/science.1188510 (2010).

    Google Scholar 

  29. Neumann, J. et al. Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis-infected macrophages. FASEB J. 24, 4599–4612. https://doi.org/10.1096/fj.10-160994 (2010).

    Google Scholar 

  30. Sun, J. et al. Crosstalk between NF-kappaB and beta-catenin pathways in bacterial-colonized intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G129–137. https://doi.org/10.1152/ajpgi.00515.2004 (2005).

    Google Scholar 

  31. van Dijk, E. M. et al. Noncanonical WNT-5B signaling induces inflammatory responses in human lung fibroblasts. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L1166–1176. https://doi.org/10.1152/ajplung.00226.2015 (2016).

    Google Scholar 

  32. Ma, B. & Hottiger, M. O. Crosstalk between Wnt/beta-Catenin and NF-kappaB signaling pathway during inflammation. Front. Immunol. 7, 378. https://doi.org/10.3389/fimmu.2016.00378 (2016).

    Google Scholar 

  33. Saadeddin, A., Babaei-Jadidi, R., Spencer-Dene, B. & Nateri, A. S. The links between transcription, beta-catenin/JNK signaling, and carcinogenesis. Mol. Cancer Res. 7, 1189–1196. https://doi.org/10.1158/1541-7786.MCR-09-0027 (2009).

    Google Scholar 

  34. Bikkavilli, R. K., Feigin, M. E. & Malbon, C. C. p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signaling by inactivation of GSK3beta. J. Cell. Sci. 121, 3598–3607. https://doi.org/10.1242/jcs.032854 (2008).

    Google Scholar 

  35. DiSabato, D. J., Quan, N. & Godbout, J. P. Neuroinflammation: the devil is in the details. J. Neurochem. 139 (Suppl 2), 136–153. https://doi.org/10.1111/jnc.13607 (2016).

    Google Scholar 

  36. Marchetti, B. et al. Parkinson’s disease, aging and adult neurogenesis: Wnt/beta-catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging Cell. 19, e13101. https://doi.org/10.1111/acel.13101 (2020).

    Google Scholar 

  37. Tanaka, T. et al. General anesthetics inhibit LPS-induced IL-1beta expression in glial cells. PLoS One. 8, e82930. https://doi.org/10.1371/journal.pone.0082930 (2013).

    Google Scholar 

  38. Panicker, N. et al. Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of parkinson’s disease. J. Neurosci. 35, 10058–10077. https://doi.org/10.1523/JNEUROSCI.0302-15.2015 (2015).

    Google Scholar 

  39. Pocivavsek, A., Burns, M. P. & Rebeck, G. W. Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 57, 444–453. https://doi.org/10.1002/glia.20772 (2009).

    Google Scholar 

  40. Zhu, L. et al. Anti-inflammatory activities of phospholipase C inhibitor U73122: Inhibition of monocyte-to-macrophage transformation and LPS-induced pro-inflammatory cytokine expression. Int. Immunopharmacol. 29, 622–627. https://doi.org/10.1016/j.intimp.2015.09.019 (2015).

    Google Scholar 

  41. Schaale, K., Neumann, J., Schneider, D., Ehlers, S. & Reiling, N. Wnt signaling in macrophages: augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur. J. Cell. Biol. 90, 553–559 (2011).

    Google Scholar 

  42. Wetzel, A. et al. Dysregulated Wnt and NFAT signaling in a parkinson’s disease LRRK2 G2019S knock-in model. Sci. Rep. 14, 12393. https://doi.org/10.1038/s41598-024-63130-8 (2024).

    Google Scholar 

  43. Clark, I. A., Alleva, L. M. & Vissel, B. The roles of TNF in brain dysfunction and disease. Pharmacol. Ther. 128, 519–548. https://doi.org/10.1016/j.pharmthera.2010.08.007 (2010).

    Google Scholar 

  44. Clark, I. A. & Vissel, B. Therapeutic implications of how TNF links Apolipoprotein E, phosphorylated tau, alpha-synuclein, amyloid-beta and insulin resistance in neurodegenerative diseases. Br. J. Pharmacol. 175, 3859–3875. https://doi.org/10.1111/bph.14471 (2018).

    Google Scholar 

  45. Di Lazzaro, G. et al. Differential profiles of serum cytokines in parkinson’s disease according to disease duration. Neurobiol. Dis. 190, 106371. https://doi.org/10.1016/j.nbd.2023.106371 (2024).

    Google Scholar 

  46. Forlenza, O. V. et al. Increased serum IL-1beta level in alzheimer’s disease and mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 28, 507–512. https://doi.org/10.1159/000255051 (2009).

    Google Scholar 

  47. Hannoush, R. N. Kinetics of Wnt-driven beta-catenin stabilization revealed by quantitative and Temporal imaging. PLoS One. 3, e3498. https://doi.org/10.1371/journal.pone.0003498 (2008).

    Google Scholar 

  48. Ito, M. et al. SP600125 inhibits cap-dependent translation independently of the c-Jun N-terminal kinase pathway. Cell. Struct. Funct. 36, 27–33. https://doi.org/10.1247/csf.10025 (2011).

    Google Scholar 

  49. Macmillan, D. & McCarron, J. G. The phospholipase C inhibitor U-73122 inhibits Ca(2+) release from the intracellular sarcoplasmic reticulum Ca(2+) store by inhibiting Ca(2+) pumps in smooth muscle. Br. J. Pharmacol. 160, 1295–1301. https://doi.org/10.1111/j.1476-5381.2010.00771.x (2010).

    Google Scholar 

  50. Schildge, S., Bohrer, C., Beck, K. & Schachtrup, C. Isolation and culture of mouse cortical astrocytes. J. Vis. Exp. https://doi.org/10.3791/50079 (2013).

    Google Scholar 

  51. Stayte, S. et al. The Kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain. Exp. Neurol. 323, 113062. https://doi.org/10.1016/j.expneurol.2019.113062 (2020).

    Google Scholar 

  52. Gundersen, H. J. & Jensen, E. B. The efficiency of systematic sampling in stereology and its prediction. J. Microsc. 147, 229–263. https://doi.org/10.1111/j.1365-2818.1987.tb02837.x (1987).

    Google Scholar 

  53. Paxinos, G. & Franklin, K. The Mouse Brain in Stereotaxic Coordinates 2 edn (Academic, 2001).

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Funding

This study was supported by The Australian Government Research Training Program Scholarship to Gabrielle Federici; The Helen and David Baffsky Fellowship to Sandy Stayte; The Boyarsky family; Andrew Michael and Michele Brooks; John and Debbie Schaffer; Richard Gelski; Alex Sundich and Bridge Street Capital Partners; Doug Battersby and family; David King and family; Harry Holden; Tony and Vivian Howland-Rose; The ISG Foundation; Stanley and Charmaine Roth; Richard, Adrian and Tom O’Connor; Marnie and Gary Perlstein; David Schwartz and Stephen Young.

Author information

Authors and Affiliations

  1. School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia

    Gabrielle Federici

  2. St Vincent’s Hospital Centre for Applied Medical Research, St Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia

    Sandy Stayte, Peggy Rentsch & Bryce Vissel

  3. School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia

    Peggy Rentsch & Bryce Vissel

Authors
  1. Gabrielle Federici
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  2. Sandy Stayte
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  3. Peggy Rentsch
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  4. Bryce Vissel
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Contributions

GF, SS, PR, and BV conceptualized the studies. GF performed all in vitro studies. GF and SS performed all in vivo studies. SS and BV provided supervision. All authors contributed to the writing of the manuscript and all authors read and approved the final manuscript.

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Correspondence to Bryce Vissel.

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Federici, G., Stayte, S., Rentsch, P. et al. Wnt-3a exacerbates production of TNF-α in LPS stimulated microglia independent of the β-catenin canonical pathway. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37653-1

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  • Received: 25 August 2025

  • Accepted: 23 January 2026

  • Published: 11 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-37653-1

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Keywords

  • Wnt-3a
  • Microglia
  • TNF-α
  • Parkinson’s disease
  • β-catenin
  • Degeneration
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