TNF-α/TNFR2 Regulatory Axis Stimulates EphB2-Mediated Neuroregeneration Via Activation of NF-κB.
HIV-1 infected individuals are at high risk of developing HIV-associated neurocognitive disorders (HAND) as HIV infection leads to neuronal injury and synaptic loss in the central nervous system (CNS). The neurotoxic effects of HIV-1 are primarily a result of viral replication leading to the production of inflammatory chemokines and cytokines, including TNF-α. Given an important role of TNF-α in regulating synaptic plasticity, we investigated the effects of TNF-α on the development of neuronal processes after mechanical injury, and we showed that TNF-α treatment stimulates the regrowth of neuronal processes. To investigate transcriptional effects of TNF-α on synaptic plasticity, we analyzed both human neurosphere and isolated neuronal cultures for the regulation of genes central to synaptic alterations during learning and memory. TNF-α treatment upregulated Ephrin receptor B2 (EphB2), which is strongly involved in dendritic arborization and synaptic integrity. TNF-α strongly activates the NF-κB pathway, therefore, we propose that TNF-α-induced neurite regrowth occurs primarily through EphB2 signaling via stimulation of NF-κB. EphB2 promoter activity increased with TNF-α treatment and overexpression of NF-κB. Direct binding of NF-κB to the EphB2 promoter occurred in the ChIP assay, and site-directed mutagenesis identified binding sites involved in TNF-α-induced EphB2 activation. TNF-α induction of EphB2 was determined to occur specifically through TNF-α receptor 2 (TNFR2) activation in human primary fetal neurons. Our observations provide a new avenue for the investigation on the impact of TNF-α in the context of HIV-1 neuronal cell damage as well as providing a potential therapeutic target in TNFR2 activation of EphB2.
Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Paul D
PD
Pozniak
Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.|Division of Neuropathology, Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York.
Armine
A
Darbinyan
Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Kamel
K
Khalili
D001665:Binding Sites; D002478:Cells, Cultured; D005865:Gestational Age; D006801:Humans; D009154:Mutation; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
C498143:RELA protein, human; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C586310:EPHB2 protein, human; D036183:Receptor, EphB2