RESUMO
Microglia maintain brain homeostasis as the main immune cells in the central nervous system. Activation of sigma-1 receptor (Sig1R) plays neuroprotective and anti-inflammatory roles in microglia. Recent studies showed that Sig1R expression level has been reduced in the brain of the patients with neurodegenerative diseases including Alzheimer's disease. However, the mechanisms underlying the down regulation of the Sig1R has not been clear. Treatment of rat primary cultured microglia with the inflammogen lipopolysaccharide (LPS) significantly decreased the expression of Sig1R mRNA in a concentration and time-dependent manner. The effects of LPS were blocked by pretreatment with TAK-242, a toll-like receptor 4 (TLR4) antagonist. Furthermore, inhibitors of transforming growth factor beta-activated kinase 1 (TAK1), p38 mitogen-activated protein kinase (MAPK) and histone deacetylase 6 (HDAC6) restored the LPS-induced downregulation of Sig1R. Thus, the current findings demonstrate that TLR4 activation leads to the downregulation of the Sig1R expression via TLR4-TAK1-p38 MAPK pathway and the inhibition of HDAC6 can increase Sig1R expression in microglia. The current findings suggest that downregulation of Sig1R may contribute to neuroinflammation-induced microglial dysfunction, regulation of microglial Sig1R may be novel therapeutic drug candidates for neurodegenerative and neuroinflammatory diseases.
Assuntos
Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Desacetilase 6 de Histona/fisiologia , MAP Quinase Quinase Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Microglia/metabolismo , Doenças Neurodegenerativas/genética , Receptores sigma/genética , Receptores sigma/metabolismo , Receptor 4 Toll-Like/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Células Cultivadas , Regulação para Baixo/genética , MAP Quinase Quinase Quinases/metabolismo , Terapia de Alvo Molecular , Doenças Neurodegenerativas/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores sigma/fisiologia , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Receptor Sigma-1RESUMO
Microglia have both protective and degenerative roles in the central nervous system. The α7 nicotinic acetylcholine receptor (nAChR) is crucial in the regulation of the neuroprotective role in microglia. Recent studies have demonstrated decreased expression of α7 nAChR in brain in response to neuroinflammation, but the mechanism mediating the downregulation of the α7 nAChR has yet to be elaborated. Treatment of microglial cell line BV2 cells or rat primary cultured microglia with the inflammogen lipopolysaccharide (LPS) significantly decreased the expression of α7 nAChR mRNA in a time and concentration-dependent manner. The effects of LPS were prevented by pretreatment with TAK-242, a toll-like receptor 4 (TLR4) blocker. The LPS-induced downregulation of α7 nAChR was also prevented with trichostatin A, a histone deacetylase (HDAC) inhibitor, but not 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. Further pharmacological probing revealed that HDAC2 and HDAC3 were involved in the effects of LPS. Treatment of BV2 cells with LPS significantly reduced acetylation of histone H3 at lysine 9 of the α7 nAChR promoter. The current findings demonstrate that inflammation-evoked activation of TLR4 leads to the reduction of the neuroprotective function of microglia through the downregulation of the α7 nAChR. Also, histone modification could be crucial in the regulation of the neuroprotective role of microglia during neuroinflammatory states.