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

Traumatic brain injury (TBI) is the leading cause of death in young adults. After the initial injury, a poorly understood secondary phase, including a strong inflammatory response determines the final outcome of TBI. The inhibitor of NF-kappa B kinase (IKK)/NF-kappa B 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-kappa B signaling pathway in TBI using an experimental model of closed-head injury (CHI) in combination with mouse models allowing conditional regulation of IKK/NF-kappa B signaling in excitatory forebrain neurons. We found that repression of IKK2/NF-kappa B signaling in neurons increases the acute posttraumatic mortality rate, worsens the neurological outcome, and promotes neuronal cell death by apoptosis, thus resulting in enhanced proinflammatory gene expression. As a potential mechanism, we identified elevated levels of the proapoptotic mediators Bax and Bad and enhanced expression of stress response genes. This phenotype is also observed when neuronal IKK/NF-kappa B activity is inhibited just before CHI. In contrast, neuron-specific activation of IKK/NF-kappa B signaling does not alter the TBI outcome. Thus, this study demonstrates that physiological neuronal IKK/NF-kappa B signaling is necessary and sufficient to protect neurons from trauma consequences.