Citation

Lian H, Shim DJ, Gaddam SS, Rodriguez-Rivera J, Bitner BR, Pautler RG, Robertson CS, Zheng H. Mol. Neurodegener. 2012; 7(1): 47.

Copyright

(Copyright © 2012, Holtzbrinck Springer Nature Publishing Group - BMC)

DOI

10.1186/1750-1326-7-47

PMID

22992283

Abstract

BACKGROUND: The transcription factor NFkappaB is an important mediator of cell survival and inflammation in the immune system. In the central nervous system (CNS), NFkappaB signaling has been implicated in regulating neuronal survival following acute pathologic damage such as traumatic brain injury (TBI) and stroke. NFkappaB is normally bound by the principal inhibitory protein, IkappaBalpha, and sequestered in the cytoplasm. Activation of NFkappaB requires the degradation of IkappaBalpha, thereby freeing NFkappaB to translocate to the nucleus and activate the target genes. Mice deficient in IkappaBalpha display deregulated and sustained NFkappaB activation and early postnatal lethality, highlighting a critical role of IkappaBalpha in NFkappaB regulation. RESULTS: We investigated the role of IkappaBalpha in regulating NFkappaB activity in the brain and the effects of the NFkappaB/IkappaBalpha pathway in mediating neuroinflammation under both physiological and brain injury conditions. We report that astrocytes, but not neurons, exhibit prominent NFkappaB activity, and that basal NFkappaB activity in astrocytes is elevated in the absence of IkappaBalpha. By generating mice with brain-specific deletion of IkappaBalpha, we show that IkappaBalpha 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. CONCLUSIONS: We conclude that, in the CNS, astrocyte is the primary cell type subject to NFkappaB regulation. We further demonstrate that IkappaBalpha plays an important role in regulating NFkappaB activity in the brain and a robust NFkappaB/IkappaBalpha-mediated neuroinflammatory response immediately following TBI is beneficial.

Language: en