UPDATEInflammasomesinneurologicaldiseases:emergingpathogenicandtherapeuticconceptsManmeetK.Mamik1andChristopherPower1,2Inflammasomeactivationinthecentralnervoussystemoccursinbothhealthanddisease.Inflammasomesarecytosolicproteincomplexesthatsensespecificinfectiousorhoststimuliandinitiateinflammatoryresponsesthroughcaspaseactivation.Assemblyofinflammasomesresultsincaspase-1-mediatedproteolyticcleavageandreleaseofthepro-inflammatorycytokines,interleukin-1bandinterleukin-18,withinitiationofpyroptosis,aninflammatoryprogrammedcelldeath.Recentdevelopmentsintheinflamma-somefieldhaveuncoverednovelmolecularmechanismsthatcontributetoabroadrangeofneurologicaldisordersincludingthoseassociatedwithspecificmutationsininflammasomegenesaswellasdiseasesmodulatedbyinflammasomeactivation.Thisupdatefocusesonrecentdevelopmentsinthefieldofinflammasomebiologyhighlightingdifferentinflammasomeactivatorsandpathwaysdiscoveredinthenervoussystem.Wealsodiscusstargetedtherapiesthatregulateinflammasomesandimproveneurologicaloutcomes.1DepartmentofMedicine(DivisionofNeurology),UniversityofAlberta,Edmonton,AB,Canada2NeuroscienceandMentalHealthInstitute,UniversityofAlberta,Edmonton,AB,CanadaCorrespondenceto:ChristopherPower,DepartmentsofMedicine,MedicalMicrobiologyandImmunology,UniversityofAlberta,611HeritageMedicalResearchCentre,Edmonton,AlbertaT6G2S2,CanadaE-mail:chris.power@ualberta.caKeywords:inflammasome;interleukin-1beta;caspase-1;ASC;pyroptosisAbbreviations:DAMP=danger-associatedmolecularpatterns;EAE=experimentalautoimmuneencephalomyelitis;PAMP=pathogen-associatedmolecularpatterns;ROS=reactiveoxygenspeciesIntroductionInflammasomeswerefirstdescribedin2002ascytosoliccaspase-activatingproteincomplexesinmacrophagelineagecells,responsiblefortheproteolyticcleavageandreleaseofthecytokinesIL-1bandIL-18aswellasadistincttypeofprogrammedcelldeath,termedpyroptosis(Martinonetal.,2002)(Fig.1).Itwassoonrecognizedthatinflammasomemachineryispresentinnumerouscelltypesandcontributestoinnateimmuneactivationinmult...
