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dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.creatorEdara, Venkata Viswanadh
dc.creatorNooka, Shruthi
dc.creatorProulx, Jessica
dc.creatorStacy, Satomi
dc.creatorGhorpade, Anuja
dc.creatorBorgmann, Kathleen
dc.identifier.citationEdara, V. V., Nooka, S., Proulx, J., Stacy, S., Ghorpade, A., & Borgmann, K. (2020). β-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes. Biomedicines, 8(11), 479.
dc.description.abstractReactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of the wingless type (Wnt)/beta-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induced mediators of the Wnt/beta-catenin pathway including beta-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of beta-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of beta-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1beta alone and in combination with TNF-alpha, strongly induced the expression of proinflammatory cytokines including C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)8 and IL-6; however, only IL-6 levels were regulated by beta-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by beta-catenin. To better understand this relationship, we examined the crossroads between beta-catenin and nuclear factor (NF)-kappaB pathways. While NF-kappaB expression was significantly increased by IL-1beta and TNF-alpha, NF-kappaB levels were not affected by beta-catenin knockdown. IL-1beta treatment significantly increased glycogen synthase kinase (GSK)-3beta phosphorylation, which inhibits beta-catenin degradation. Further, pharmacological inhibition of GSK-3beta increased nuclear translocation of both beta-catenin and NF-kappaB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, beta-catenin and NF-kappaB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases beta-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that beta-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND.
dc.description.sponsorshipThis research was funded by National Institute of Mental Health, grant number R21 MH113452 and the JES Edwards Foundation of Fort Worth. We appreciate the assistance of the Laboratory of Developmental Biology at UW in Seattle for providing human brain tissues, supported by NIH 5R24 HD0008836 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
dc.subjectHIV-associated neurocognitive disorders (HAND), IL-6 regulation
dc.subjectNF-kappaB crosstalk
dc.subjectWnt/beta-catenin signaling
dc.titleβ-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes
dc.rights.holderCopyright © 2020 by the authors.
dc.creator.orcid0000-0003-0897-390X (Borgmann, Kathleen)
dc.creator.orcid0000-0001-9321-7839 ( Edara, Venkata Viswanadh)
dc.creator.orcid0000-0002-5452-0461 (Proulx, Jessica)

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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's license is described as Attribution 4.0 International (CC BY 4.0)