Abstract
The ethanol-induced toll-like receptor 4 (TLR4) signal activation of microglia and neuroinflammation are observed in both adolescent and adult rat brains, but the regulatory mechanisms of some TLR4 signaling-related factors in this process are still unclear. SUMO-specific protease 6 (SENP6) inhibits neuroinflammation by dampening nuclear factor kappa-B (NF-κB) activation via the de-SUMOylation of NF kappa-B essential modulator (NEMO). This study investigates the effects of long-term ethanol consumption on neuroinflammation in the hippocampus of adolescent rats and the regulatory roles of TLR4 and SENP6. Twenty-one days of ethanol exposure in adolescent rats were used to develop an animal model. The number of microglia, microglial activation, and the expression of TLR4 in the hippocampus of adolescent rats were examined by immunoreactivity. The levels of TLR4, activation of NF-κB including IkB-α and p-NF-κB-p65, and SENP6 were measured by western blotting. Proinflammatory cytokines including TNF-α, IL-1β, and IL-6 were measured by enzyme-linked immunosorbent assay. The NF-κB activation and proinflammatory cytokines released in overexpressed SENP6 and siRNA targeting SENP6 microglial cells after treatment with ethanol were estimated in vitro. This study found that alcohol exposure increased the number of activated microglia and the levels of p-NF-κB-p65 and proinflammatory cytokines, while it decreased the SENP6 level in wild-type rats, but not in TLR4 knockout rats. The ethanol-induced increases of p-NF-κB-p65, TNF-α, and IL-1β were dampened by overxpression of SENP6 and enhanced in SENP6-siRNA microglia. Our data suggest that ethanol exposure during adolescence induces the microglia-mediated neuroinflammation via TLR4 activation, and SENP6 plays an essential role in dampening NF-κB activation and neuroinflammation.
Highlights
The percentage of alcohol consumption in adolescents is increasing [1]
The results indicate that ethanol exposure increases Iba-1 immunoreactivity of microglia in the adolescent rat hippocampus depending on toll-like receptor 4 (TLR4) activation
The results indicated that ethanol exposure decreased SENP6 expression and activated NF-κB inflammatory signaling via TLR4 activation
Summary
The percentage of alcohol consumption in adolescents is increasing [1]. Among the subregions of the brain, the adolescent hippocampus is vulnerable to alcohol-induced structural damage which results in behavioral deficits [5, 6]. Hippocampal neurogenesis, a process that continues throughout life and contributes significantly to structural and functional aspects of the hippocampus, is inhibited by alcohol exposure [9, 10]. Neuroinflammation is hypothesized to be one pathogenetic process leading to alcoholic brain damage [13,14,15]. In the process of ethanol-induced neuroinflammation, activation of microglia plays a pivotal role through toll-like receptor 4 (TLR4) activation [15,16,17]
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