Abstract
Reactive 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)/β-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α induced mediators of the Wnt/β-catenin pathway including β-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of β-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of β-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1β alone and in combination with TNF-α, 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 β-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by β-catenin. To better understand this relationship, we examined the crossroads between β-catenin and nuclear factor (NF)-κB pathways. While NF-κB expression was significantly increased by IL-1β and TNF-α, NF-κB levels were not affected by β-catenin knockdown. IL-1β treatment significantly increased glycogen synthase kinase (GSK)-3β phosphorylation, which inhibits β-catenin degradation. Further, pharmacological inhibition of GSK-3β increased nuclear translocation of both β-catenin and NF-κB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, β-catenin and NF-κB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases β-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that β-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND.
Highlights
More than 30% of human immunodeficiency virus-1 (HIV-1) positive patients develop disorders associated with the central nervous system (CNS) [1,2]
HIV-1 infection of macrophages and microglia in the CNS leads to cellular activation and secretion of neurotoxic cytokines such as IL-1β and tumor necrosis factor (TNF)-α [10,11]
To investigate how IL-1β and TNF-α affect wingless type (Wnt)/β-catenin and nuclear factor (NF)-κB signaling during HIV-associated neuroinflammation, human astrocyte cultures were exposed to the pro-inflammatory cytokines IL-1β (20 ng/mL) and TNF-α
Summary
More than 30% of human immunodeficiency virus-1 (HIV-1) positive patients develop disorders associated with the central nervous system (CNS) [1,2]. Multiple studies have shown upregulation of inflammatory cytokines such as C-X-C motif chemokine ligand (CXCL), C-C motif chemokine ligand (CCL), CCL3, interferon (IFN)-γ and IL-6 production by astrocytes in response to macrophage-derived IL-1β and TNF-α during HIV-1 CNS infection [15,16,17,18]. These cytokines indirectly mediate their neurotoxic effects by activating astrocytes and play an important role in the further induction of neuronal injury and HAND pathogenesis [19,20,21,22]. We investigated the regulatory mechanisms mediated by Wnt/β-catenin signaling in the neuroinflammation-associated reactive astrogliosis process
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