Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death

Abstract

Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikkbeta conditional knockout mice (LysM-Cre/Ikkbeta(F/F)) in which the Ikkbeta gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IkappaB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikkbeta(F/F)), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/Ikkbeta(F/F) mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikkbeta(F/F) mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-alpha and IL-1beta expression. Based on these data, we concluded that IKK/nuclear factor-kappaB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.

Inflammatory Mediators as Biomarkers in Brain Disorders

“…These animals also express high levels of inflammatory cytokines including IL-6, IL-1β, and TNF-α in the serum and CNS, which is consistent with a deregulated IKKβ/NF-κB pathway [72]. A recent study [74] supports a role for IKKβ in neuroinflammation and highlights that imbalances in IKKβ activity may be the underlying cause of elevated cytokines in the CNS of HD patients. In these works, the authors observed that the inhibition of caspase-mediated maturation of IL-1β enhances neuroinflammation and neurotoxicity in a mouse model and the lowering of IKKβ in microglia reduces inflammation and neurotoxicity in to kainic acid-induced excitotoxicity model of HD.…”

Betulinic Acid Inhibits LPS-Induced MMP-9 Expression by Suppressing NF-kB Activation in BV2 Microglial Cells

“…NF-kB-dependent microglial activation has been reported to be a crucial contributor to ischemia (Cho et al, 2008). In the present study, betulinic acid signifi cantly attenuated LPS-induced nuclear translocation of NF-kB and subsequent extracellular releases of pro-infl ammatory cytokines and MMP-9, through the inhibition of LPS-induced IKB degradation.…”

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

“…23 Suppression of NFkB attenuates microglial activation, thereby rendering the neuroprotection. 24,25 We found that, in the Jmjd3-knockdown N9 cells, the phosphorylation of NFkB was significantly enhanced, which might contribute to amplify the pro-inflammation (Figures 3e and f). Collectively, suppression of Jmjd3 compromises M2 microglia polarization and accordingly leads to exaggerated M1 microglial inflammatory responses.…”