Abstract
BackgroundThe transcription factor NFκB is an important mediator of cell survival and inflammation in the immune system. In the central nervous system (CNS), NFκB signaling has been implicated in regulating neuronal survival following acute pathologic damage such as traumatic brain injury (TBI) and stroke. NFκB is normally bound by the principal inhibitory protein, IκBα, and sequestered in the cytoplasm. Activation of NFκB requires the degradation of IκBα, thereby freeing NFκB to translocate to the nucleus and activate the target genes. Mice deficient in IκBα display deregulated and sustained NFκB activation and early postnatal lethality, highlighting a critical role of IκBα in NFκB regulation.ResultsWe investigated the role of IκBα in regulating NFκB activity in the brain and the effects of the NFκB/IκBα pathway in mediating neuroinflammation under both physiological and brain injury conditions. We report that astrocytes, but not neurons, exhibit prominent NFκB activity, and that basal NFκB activity in astrocytes is elevated in the absence of IκBα. By generating mice with brain-specific deletion of IκBα, we show that IκBα deficiency does not compromise normal brain development. However, basal neuroinflammation detected by GFAP and Iba1 immunoreactivity is elevated. This leads to impaired inflammatory responses following TBI and worsened brain damage including higher blood brain barrier permeability, increased injury volumes and enlarged ventricle volumes.ConclusionsWe conclude that, in the CNS, astrocyte is the primary cell type subject to NFκB regulation. We further demonstrate that IκBα plays an important role in regulating NFκB activity in the brain and a robust NFκB/IκBα-mediated neuroinflammatory response immediately following TBI is beneficial.
Highlights
The transcription factor NFκB is an important mediator of cell survival and inflammation in the immune system
We show that IκBα deficiency leads to elevated basal neuroinflammation, resulting in a failure to mount proper inflammatory responses following traumatic brain injury (TBI) and worsened brain damage
Deletion of IκBα in the brain leads to upregulated astroglia NFκB activity and neuroinflammation We generated mice with specific deletion of IκBα in the brain (IκBα cKO) by crossing an IκBα floxed allele [26] with the Nestin-Cre [27] transgenic mice (Figure 1A)
Summary
The transcription factor NFκB is an important mediator of cell survival and inflammation in the immune system. In the central nervous system (CNS), NFκB signaling has been implicated in regulating neuronal survival following acute pathologic damage such as traumatic brain injury (TBI) and stroke. Following the primary mechanical insults, TBI induces a multifactorial tissue response, including the breakdown of blood–brain barrier (BBB) and activation of inflammatory pathways, within hours to days following the trauma, and these have been shown to influence the neuronal survival and functional recovery (reviewed in [3]). In mouse and rat models of TBI, some studies show that the cytokine release promotes BBB breakdown and worsens brain damage and functional outcome [6,7,8,9,10], while other reports suggest that some aspects of inflammation may be beneficial to the brain [4,11,12,13,14]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call