HDAC6 Regulates LPS-Tolerance in Astrocytes 英文参考文献.docVIP

HDAC6RegulatesLPS-ToleranceinAstrocytes Ele′onoreBeurel* DepartmentofPsychiatryandBehavioralSciences,UniversityofMiami,Miami,Florida,UnitedStatesofAmerica Abstract Inflammatorytoleranceisacrucialmechanismthatlimitsinflammatoryresponsesinordertoavoidprolongedinflammation that may damage the host. Evidence that chronic inflammation contributes to the neuropathology of prevalent neurodegenerative and psychiatric diseases suggests that inflammatory tolerance mechanisms are often inadequate to control detrimental inflammation in the central nervous system. Thus, identifying mechanisms that regulate neuroinflammatory tolerance may reveal opportunities for bolstering tolerance to reduce chronic inflammation in these diseases. Examination of tolerance after repeated lipopolysaccharide (LPS) treatment of mouse primary astrocytes demonstratedthathistonedeacetylase(HDAC)activitypromotedtolerance,oppositetotheactionofglycogensynthase kinase-3 (GSK3), which counteractstolerance. HDAC6in particular was foundtobe critical for toleranceinduction, asits deacetylation of acetyl-tubulin was increased during LPS tolerance, this was enhanced by inhibition of GSK3, and the HDAC6inhibitortubacincompletelyblockedtoleranceandthepromotionoftolerancebyinhibitionofGSK3.Theseresults reveal opposing interactions between HDAC6 and GSK3 in regulating tolerance, and indicate that shifting the balance betweenthesetwoopposingforcesoninflammatorytolerancecanobliterateorenhancetolerancetoLPSinastrocytes. Citation:BeurelE(2011)HDAC6RegulatesLPS-ToleranceinAstrocytes.PLoSONE6(10):e25804.doi:10.1371/journal.pone.0025804 Editor:GuenterSchneider,TechnischeUniversita¨t Mu¨nchen,Germany ReceivedJune23,2011;AcceptedSeptember11,2011;PublishedOctober12,2011 Copyright: ?2011 Ele′onore Beurel. This isan open-access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredite