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IκBα deficiency in brain leads to elevated basal neuroinflammation and attenuated response following traumatic brain injury: implications for functional recovery.

Lian H, Shim DJ, Gaddam SS, Rodriguez-Rivera J, Bitner BR, Pautler RG, Robertson CS, Zheng H - Mol Neurodegener (2012)

Bottom Line: 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.We conclude that, in the CNS, astrocyte is the primary cell type subject to NFκB regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Huffington Center on Aging Baylor College of Medicine, Houston, TX 77030, USA.

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusions: We 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.

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Elevated neuroinflammation in IκBα cKO mice. (A and C) Representative images of brain sections from 10–15 month-old mice Ctrl and IκBα cKO mice stained against astroglia marker GFAP and microglia marker Iba1. HPC: hippocampus. CTX: cortex. (B and D) Quantification of GFAP- and Iba1- positive cells in HPC and CTX respectively. N = 4/genotype. For each mouse, 3 evenly spaced sections were stained and quantified. ***p < 0.001. Scale bar: 20 μm.
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Figure 3: Elevated neuroinflammation in IκBα cKO mice. (A and C) Representative images of brain sections from 10–15 month-old mice Ctrl and IκBα cKO mice stained against astroglia marker GFAP and microglia marker Iba1. HPC: hippocampus. CTX: cortex. (B and D) Quantification of GFAP- and Iba1- positive cells in HPC and CTX respectively. N = 4/genotype. For each mouse, 3 evenly spaced sections were stained and quantified. ***p < 0.001. Scale bar: 20 μm.

Mentions: Considering that NFκB is a master regulator of inflammatory responses, we tested the levels of neuroinflammation in IκBα cKO mice by immunostaining the brain sections with antibodies against GFAP and Iba1 and quantifying the number of astrocytes and microglia respectively (Figure 3). Indeed, the number of GFAP- and Iba1-positive cells in both the hippocampus (HPC) and cortex (CTX) are significantly increased in IκBα cKO brains as compared to their littermate controls (Figure 3B and D).


IκBα deficiency in brain leads to elevated basal neuroinflammation and attenuated response following traumatic brain injury: implications for functional recovery.

Lian H, Shim DJ, Gaddam SS, Rodriguez-Rivera J, Bitner BR, Pautler RG, Robertson CS, Zheng H - Mol Neurodegener (2012)

Elevated neuroinflammation in IκBα cKO mice. (A and C) Representative images of brain sections from 10–15 month-old mice Ctrl and IκBα cKO mice stained against astroglia marker GFAP and microglia marker Iba1. HPC: hippocampus. CTX: cortex. (B and D) Quantification of GFAP- and Iba1- positive cells in HPC and CTX respectively. N = 4/genotype. For each mouse, 3 evenly spaced sections were stained and quantified. ***p < 0.001. Scale bar: 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473257&req=5

Figure 3: Elevated neuroinflammation in IκBα cKO mice. (A and C) Representative images of brain sections from 10–15 month-old mice Ctrl and IκBα cKO mice stained against astroglia marker GFAP and microglia marker Iba1. HPC: hippocampus. CTX: cortex. (B and D) Quantification of GFAP- and Iba1- positive cells in HPC and CTX respectively. N = 4/genotype. For each mouse, 3 evenly spaced sections were stained and quantified. ***p < 0.001. Scale bar: 20 μm.
Mentions: Considering that NFκB is a master regulator of inflammatory responses, we tested the levels of neuroinflammation in IκBα cKO mice by immunostaining the brain sections with antibodies against GFAP and Iba1 and quantifying the number of astrocytes and microglia respectively (Figure 3). Indeed, the number of GFAP- and Iba1-positive cells in both the hippocampus (HPC) and cortex (CTX) are significantly increased in IκBα cKO brains as compared to their littermate controls (Figure 3B and D).

Bottom Line: 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.We conclude that, in the CNS, astrocyte is the primary cell type subject to NFκB regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Huffington Center on Aging Baylor College of Medicine, Houston, TX 77030, USA.

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusions: We 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.

Show MeSH
Related in: MedlinePlus