IKK2/NF-κB signaling protects neurons after traumatic brain injury

Abstract

Traumaticbraininjury (TBI) is the leading causeofdeathinyoung adults.After the initial injury, apoorly understood secondary phase, including a strong inflammatory response determines the final outcome of TBI. The inhibitor of NF-κB kinase (IKK)/NF-κB signaling system is the key regulator of inflammation and also critically involved in regulation of neuronal survival and synaptic plasticity. We addressed the neuron-specific function of IKK2/NF-κB signaling pathway in TBI using an experimental model of closed-head injury (CHI) in combination with mouse models allowing conditional regulation of IKK/NF-κB signaling in excitatory forebrain neurons. We found that repression of IKK2/NF-κB signaling in neurons increases the acute posttraumaticmortality rate,worsens the neurological outcome, and promotes neuronal cell death by apoptosis, thus resulting in enhanced proinflammatory gene expression.As a potentialmechanism,we identified elevated levels of the proapoptoticmediators Bax and Bad and enhanced expression of stress response genes. This phenotype is also observed when neuronal IKK/NF-κBactivity is inhibitedjustbeforeCHI. Incontrast, neuron-specific activationof IKK/NF-κBsignaling does not alter the TBI outcome. Thus, this study demonstrates that physiological neuronal IKK/NF-κB signaling is necessary and sufficient to protect neurons from trauma consequences.