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. J. Cell. Physiol. 231: 1237–1248, 2016. © 2015 Wiley Periodicals, Inc.