TLR4-TAK1-p38 MAPK pathway and HDAC6 regulate the expression of sigma-1 receptors in rat primary cultured microglia.
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.
['Iwamoto|Momoka|M|', 'Nakamura|Yoki|Y|', 'Takemura|Masatoshi|M|', 'Hisaoka-Nakashima|Kazue|K|', 'Morioka|Norimitsu|N|']
D000818:Animals D002478:Cells, Cultured D015536:Down-Regulation D015870:Gene Expression D005786:Gene Expression Regulation D000073864:Histone Deacetylase 6 D020930:MAP Kinase Kinase Kinases D020935:MAP Kinase Signaling System D017628:Microglia D058990:Molecular Targeted Therapy D019636:Neurodegenerative Diseases D012333:RNA, Messenger D051381:Rats D017480:Receptors, sigma D051197:Toll-Like Receptor 4 D048051:p38 Mitogen-Activated Protein Kinases
Sigma-1 receptor Microglia Toll-like receptor 4 p38 mitogen-activated protein kinase Histone deacetylase 6