TNF‐α/TNFR2 Regulatory Axis Stimulates EphB2‐Mediated Neuroregeneration Via Activation of NF‐κB

Abstract

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-alpha. Given an important role of TNF-alpha in regulating synaptic plasticity, we investigated the effects of TNF-alpha on the development of neuronal processes after mechanical injury, and we showed that TNF-alpha treatment stimulates the regrowth of neuronal processes. To investigate transcriptional effects of TNF-alpha 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-alpha treatment upregulated Ephrin receptor B2 (EphB2), which is strongly involved in dendritic arborization and synaptic integrity. TNF-alpha strongly activates the NF-kappaB pathway, therefore, we propose that TNF-alpha-induced neurite regrowth occurs primarily through EphB2 signaling via stimulation of NF-kappaB. EphB2 promoter activity increased with TNF-alpha treatment and overexpression of NF-kappaB. Direct binding of NF-kappaB to the EphB2 promoter occurred in the ChIP assay, and site-directed mutagenesis identified binding sites involved in TNF-alpha-induced EphB2 activation. TNF-alpha induction of EphB2 was determined to occur specifically through TNF-alpha receptor 2 (TNFR2) activation in human primary fetal neurons. Our observations provide a new avenue for the investigation on the impact of TNF-alpha in the context of HIV-1 neuronal cell damage as well as providing a potential therapeutic target in TNFR2 activation of EphB2.

EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis in mice via activation of hepatic stellate cells

“…Indeed we noticed that EphB2-deficient mice have a drastic reduction of proinflammatory cytokines and chemokines responsible for the maintenance of a profibrotic state in injured liver 43 , 44 . Our data corroborate recent findings linking EphB2 activation with the regulation of TNFα/NF-κB axis in hepatocytes 26 as well as in CNS diseases 45 and this strengthens the possible crosstalk between both the EphB2/NF-κB (pro-inflammatory state) and EphB2/TGF-β (pro-fibrotic state) signaling axes. Further research is needed to understand how activation of the EphB2/EphrinB signaling modulate both the NF-κB and TGF-β signaling pathways.…”

Interleukin‐1β influences functional regeneration following nerve injury in mice through nuclear factor‐κB signaling pathway

“…The NF‐ κ B signaling pathway was also put forward according to the bioinformatics analysis because it was enriched at the beginning of neural injury and decreased together with IL‐1 β . In accordance of the KEGG database, IL‐1 β could regulate the expression of several genes through the NF‐ κ B signaling pathway like TNF‐ α and COX2, which were also considered to have connections with neural regeneration . However, it had thought that IL‐1 β contributed to neurite outgrowth through the p38 MAPK pathway and the janus kinase/signal transducer and activator of tran‐ions (JAK/STAT) pathway, implicating that the regenerating process might be highly complicated.…”

Toll-like receptor 3 modulates the behavioral effects of cocaine in mice

“…However, there are still many other factors in the immune system that can mediate NF-κB activity, such as the TLRs, TNFR family, and IL-1R [ 57 , 58 ]. In central nervous system, TNF-α/TNFR2-induced neurite regrowth occurs primarily through EphB2 signaling via NF-κB activation [ 59 ]. However, one study reported that microglial TNF-α suppresses cocaine-induced neuroplasticity and behavioral sensitization [ 60 ].…”