1、UPDATEInflammasomes in neurological diseases:emerging pathogenic and therapeutic conceptsManmeet K.Mamik1and Christopher Power1,2Inflammasome activation in the central nervous system occurs in both health and disease.Inflammasomes are cytosolic proteincomplexes that sense specific infectious or host
2、 stimuli and initiate inflammatory responses through caspase activation.Assembly ofinflammasomes results in caspase-1-mediated proteolytic cleavage and release of the pro-inflammatory cytokines,interleukin-1band interleukin-18,with initiation of pyroptosis,an inflammatory programmed cell death.Recen
3、t developments in the inflamma-some field have uncovered novel molecular mechanisms that contribute to a broad range of neurological disorders including thoseassociated with specific mutations in inflammasome genes as well as diseases modulated by inflammasome activation.This updatefocuses on recent
4、 developments in the field of inflammasome biology highlighting different inflammasome activators and pathwaysdiscovered in the nervous system.We also discuss targeted therapies that regulate inflammasomes and improve neurologicaloutcomes.1 Department of Medicine(Division of Neurology),University of
5、 Alberta,Edmonton,AB,Canada2 Neuroscience and Mental Health Institute,University of Alberta,Edmonton,AB,CanadaCorrespondence to:Christopher Power,Departments of Medicine,Medical Microbiology and Immunology,University of Alberta,611 Heritage Medical Research Centre,Edmonton,Alberta T6G 2S2,CanadaE-ma
6、il:chris.powerualberta.caKeywords:inflammasome;interleukin-1beta;caspase-1;ASC;pyroptosisAbbreviations:DAMP=danger-associated molecular patterns;EAE=experimental autoimmune encephalomyelitis;PAMP=pathogen-associated molecular patterns;ROS=reactive oxygen speciesIntroductionInflammasomes were first d
7、escribed in 2002 as cytosoliccaspase-activating protein complexes in macrophage lineagecells,responsible for the proteolytic cleavage and release ofthe cytokines IL-1b and IL-18 as well as a distinct type ofprogrammed cell death,termed pyroptosis(Martinon et al.,2002)(Fig.1).It was soon recognized t
8、hat inflammasomemachinery is present in numerous cell types and contributesto innate immune activation in multiple organs includingthe CNS(Bergsbaken et al.,2009).Innate immunity is anintegral component of neuroinflammation and is recognizedas both a causative and consequential aspect of manyneurolo
9、gicaldiseases(Henekaetal.,2014).Innateimmune responses including inflammasome activation areinitiated by host recognition of pathogen-associated mo-lecular patterns(PAMPs)expressed on microbial pathogens(e.g.bacteria,viruses,parasites)or by danger-associatedmolecular patterns(DAMPs)produced by host
10、cells e.g.ATP,DNA,reactive oxygen species(ROS)(Kannegantiet al.,2006;Martinon and Tschopp,2007).These mol-ecules serve as ligands for pattern-recognition receptors ex-pressed on cells of the innate immune system,includingmicroglia,macrophagesandastrocytesintheCNS(Bryant and Fitzgerald,2009).Binding
11、of PAMPs orDAMPstopattern-recognitionreceptorsinducesdoi:10.1093/brain/awx133BRAIN 2017:Page 1 of 13|1Received December 19,2016.Revised April 11,2017.Accepted April 15,2017.?The Author(2017).Published by Oxford University Press on behalf of the Guarantors of Brain.All rights reserved.For Permissions
12、,please email:inflammasome gene transcription and assembly providingplatforms for proteolytic cleavage and subsequent releaseof IL-1b and IL-18(Fig.2).Both cytokines are present incells as inactive precursors(pro-IL-1b and IL-18)and re-quirecaspase-1-mediatedcleavageforconversionintoactive forms.Pro
13、-caspase-1 undergoes autocatalysis duringinflammasomeactivationtoyieldactivecaspase-1(Martinon et al.,2002;Dagenais et al.,2012).Caspases-4and 5 were shown to mediate IL-1b release via one-stepnon-canonical inflammasome activation(Vigano et al.,2015).Recent reviews have enhanced our understandingof
14、the role of inflammasomes in CNS disease(Freemanand Ting,2016;Kong et al.,2016).In this comprehensiveupdate,we highlight the major new developments in CNSinflammasome research encompassing a broader spectrumof neurological diseases in the context of both pathogenesisand therapy.Inflammasomes:biology
15、 andmechanisms of activationInflammasomes contain different structural domains thatmediate individual functions(Fig.1).Nucleotide-bindingdomain(NB)and leucine-rich repeat(LRR)containing re-ceptors(NLR),also called NOD-like receptors,are cytosolicpattern-recognition receptors found chiefly in macroph
16、age-like cells.More than 20 NLR proteins have been identifiedto date.NLRs contain an N-terminal effector bindingdomain(e.g.PYD,CARD),a nucleotide-binding oligomer-ization domain(NACHT),and a C-terminal LRR receptordomain,which binds to ligands and leads to activation ofinflammasomes(Kita et al.,2009
17、).Most inflammasomeshave ASC(apoptosis-associated speck-like protein,encodedby PYCARD)as an adaptor molecule,which translocates toFigure 1Inflammasome components and actions.Inflammasomes are activated by one or more signals resulting in assembly of individualinflammasomes that provide a platform fo
18、r caspase-1 autocatalysis and activation.Activated caspase-1 mediates proteolytic cleavage and release ofIL-1b and IL-18.Additionally,caspase-1 also cleaves gasdermin D,which forms pores in the membrane,contributing to pyroptosis.2|BRAIN 2017:Page 2 of 13M.K.Mamik and C.Powerthe cytoplasm in respons
19、e to stimuli to form specks andrecruit caspase-1.Caspase-1 activation also cleaves gasder-min D(GSDMD)to active N-terminal GSDMD causing it toform cytotoxic pores in cell membrane,driving the cell to-wards pyroptosis(Shi et al.,2017)(Fig.1).Inflammasomes in thenervous systemMicroglia,neurons,oligode
20、ndrocytes,astrocytes and Schwanncells can exert immune actions depending on the circum-stances although neurons and oligodendrocytes are not usu-ally regarded as immune effector cells.Basal levels of IL-1band IL-18 are essential for physiological functions of the ner-vous system and cytokine deficie
21、ncies can result in adverseoutcomes(Dinarello,2007;Blok et al.,2014).These cytokinesparticipate in molecular and cellular mechanisms linked tolearning,memory and sensory functions(Netea et al.,2006;McAfoose and Baune,2009).There is cell-specific expressionof inflammasome components in the nervous sy
22、stem withNLRP1,NLRP3,NLRC4 found primarily in microglia(Cho et al.,2014;Denes et al.,2015),NLRP2 and NLRP3in astrocytes(Minkiewicz et al.,2013;Lu et al.,2014)andAIM2 and NLRP1 in neurons(Adamczak et al.,2014;Tanet al.,2014)(Supplementary Fig.1).The NLRP3 inflamma-some is the most abundant inflammaso
23、me in the CNS andone of the key contributors to neuroinflammation in a broadspectrum of nervous system disorders and,therefore,the mostextensively investigated inflammasome(Song et al.,2017).Expression of specific inflammasome proteins awaits furtheranalyses for oligodendrocytes and Schwann cells.Pr
24、imary microglia respond to similar stimuli as haemato-poietic macrophages but microglial responses are more sus-tained due to lack of negative regulation of pro-IL-1bexpression(Burm et al.,2015).Microglia are the primaryproducers of IL-1b,following NLRP3 upregulation,in adepression model in rats(Pan
25、 et al.,2014).Human astro-cytes express a novel NLRP2 inflammasome,activated byATP.NLRP2 assembly and activation is mediated by theP2X7 receptor and the pannexin 1 channel leading todownstream activation of caspase-1 and ensuing IL-1b pro-duction(Minkiewicz et al.,2013).Neurons sense dangerstimuli o
26、f mechanical,thermal or chemical nature.Theyareknowntoexpressseveralinflammasomeproteinsincluding NLRP1,NLRP3 and AIM2(Kummer et al.,2007;Kaushal et al.,2015).However,the consequencesof inflammasome activation in neurons awaits further in-vestigation(Santoni et al.,2015).Endogenous regulation ofinfl
27、ammasomesWhile PAMPs and DAMPs drive inflammasome activation,individual inflammasomes can be modulated by endogenousand exogenous mechanisms(Fig.2).For example,the cyclo-pentenone prostaglandin 15d-PGJ2 inhibits NLRP1 andNLRP3 inflammasomes(Maier et al.,2015).ProstaglandinE2 restricts activation of
28、the NLRP3 inflammasome throughintracellularcyclicAMPinhumanmacrophages(Sokolowska et al.,2015).The NLRP3 inflammasome isalso regulated by multiple microRNAs at different stagesof protein assembly and activation;an inverse relationshipbetween miR-223 and NLRP3 activation was reported,sug-gesting that
29、 miR-223 offered a novel therapeutic approachfollowing intracerebral haemorrhage(Yang et al.,2015).Inanother study,miR-133a-1 suppressed inflammasome acti-vation by downregulating uncoupling protein 2(UCP2).miR-133A-1 prevented inflammasome activation without af-fecting the basal expression of NLRP3
30、,ASC,pro-IL-1b orpro-caspase-1(Bandyopadhyay et al.,2013).miR-7 re-pressed NLRP3 activation in microglia with important im-plications for Parkinsons disease(Zhou et al.,2016).Other endogenous inhibitors of inflammasomes include IL-37 and type 1 interferons(IFNs).IL-37 is a 30kDa memberof the IL-1 fa
31、mily of ligands and shares amino acid sequenceswith IL-18.It binds to the IL-18 receptor in a non-competi-tive manner and exerts anti-inflammatory effects by translo-cating to the nucleus and also inhibiting expression of IL-1b(Bulau et al.,2014).The inhibitory effects of IL-37 have beenconfirmed in
32、 bone marrow-derived macrophages and neutro-phils(Moretti et al.,2014).The type 1 IFNs including IFN?and-b exert anti-proliferative and antimicrobial actions whilealso contributing to neuropsychiatric disorders(depression,psychosis,neurocognitiveimpairments)(Robaeysetal.,2007;Capuron and Miller,2011
33、).Inflammasome activation in the CNS has important im-plications for neurological disease involving neuroinflam-mation.Below we review acute and chronic neurologicaldiseases,for which there is detailed fundamental and clin-ical evidence of inflammasome involvement.In addition,otherneurologicaldiseas
34、esforwhichmechanismsofinflammasome activation are under investigation are sum-marized in Table 1.Inflammasome activation inacute neurological diseasesStrokeStroke causes 10%of deaths worldwide and results inlong-termdisabilityinsurvivors.Inflammationduringstroke begins with secretion of pro-inflamma
35、tory cytokines(e.g.IL-1b and IL-18)by activated glial cells(Fann et al.,2013b).This primary response is followed by secondaryinfiltration of neutrophils and monocytes from the vascularcirculation,which secrete cytokines and other cytotoxicagentsincludingROSandmatrixmetalloproteinases(MMPs)(Jin et al
36、.,2010).Both NLRP1 and NLRP3 aremajor sensors of reduced intracellular ATP(Liao andInflammasomes in neurological diseaseBRAIN 2017:Page 3 of 13|3Mogridge,2013;Nomura et al.,2015).Diminished ATPactivates AMPK(AMP-activated protein kinase),which inturn activates NLRP1.Interestingly,AMPK activation isi
37、nsufficient to induce NLRP1 inflammasome activationbut lower ATP concentrations are a co-requirement,sug-gesting that ATP in physiological circumstances might in-hibit NLRP1(Liao and Mogridge,2013).High cytosolic Ca2+with reduced K+concentrations ac-tivates NLRP3 during stroke.Lower ATP results in a
38、ber-rant function of the Na+/K+-ATPase pump that causes animbalance in ionic concentrations and eventual NLRP1 andNLRP3 inflammasome activation(Munoz-Planillo et al.,2013;Rajamaki et al.,2013).MeningitisBacterial meningitis,caused by Streptococcus pneumoniae,carries a mortality rate of 1637%,with ap
39、proximatelyhalfofthesurvivorssufferingneurologicaldisability(Hoogman et al.,2007).CSF from patients with pneumo-coccal meningitis shows upregulation of caspase-1 activityaswellasIL-1bandIL-18(Hoegenetal.,2011).Correlation of elevated IL-1b and IL-18 levels with menin-gitis severity and associated co
40、mplications has been re-ported(Zwijnenburg et al.,2001).Interestingly,ASC andNLRP3 knockout mice exhibited decreased bacterial loadsbut NLRP3 expression was neuroprotective in this infectionmodel.NLRP3 knockout mice showed increased leucocyteinfiltration and cerebral haemorrhage following bacteriali
41、nfection with worsened outcomes(Geldhoff et al.,2013).In fact,IL-1 receptor knockout mice were more susceptibleto developing meningitis.Increased mortality and enhancedgrowth of pneumococci in IL-1R?/?mice was observedcompared with wild-type mice(Zwijnenburg et al.,2003).These studies emphasize the
42、beneficial effects of IL-1 signal-ling in bacterial clearance.Figure 2Inducers and inhibitors of inflammasomes in the nervous system.Exogenous PAMPs and extracellular DAMPs(LPS/MDP,TNF?,ATP,HMGB1)activate TLR4,TNFR-1 and P2X7R on the surface on innate immune cells within the nervous system including
43、 residentmicroglia,trafficking macrophages and astrocytes.Ligand binding to receptors initiates intracellular cascades prompting transcription factors(NF-?B)to translocate to the nucleus.Transcription drives expression of inflammasome components(NLRP3,AIM2)and cytokine precursors(pro-IL-1b and IL-18
44、)(Signal 1).Endogenous DAMPs or alarmins(e.g.ROS,dsDNA,ATP)activate cytosolic sensors signalling inflammasome assembly(Signal 2).NLRP3 activation is followed by adaptor protein ASC interactions and eventually proteolytic cleavage of pro-caspase-1.Functionaldomains of inflammasome components include
45、CARDs which are present in both caspase-1 and ASC and thus align during inflammasomeassembly.Pro-IL-1b and IL-18 are substrates for active caspase-1,releasing IL-1b and IL-18 into extracellular environments.Inflammasomeactivation is inhibited by type 1 interferons,IL-37 and several microRNAs.LPS=lip
46、opolysaccharide.4|BRAIN 2017:Page 4 of 13M.K.Mamik and C.PowerZika infectionZika virus(ZIKV)is a mosquito-borne flavivirus,wide-spreadinNorthAfrica,SoutheastAsiaandSouthAmerica,and is associated with meningoencephalitis inhuman foetuses and Guillain-Barre Syndrome in adults(Munoz et al.,2016).ZIKV i
47、nfection of skin fibroblasts ac-tivates AIM2 and IL-1b at the transcript level(Hamel et al.,2015).Recent studies suggest that astrocytes are the princi-pal reservoir for ZIKV(Nowakowski et al.,2016).Increasedexpression of IL-18,IL-6 and TNF?were observed in serafrom ZIKV-infected mice(Zmurko et al.,
48、2016).ZIKV in-fection increased IL-1b,NLRP3 and caspase-1 transcripts inglial cell line,leading to cell death(Tricarico et al.,2017).Thus,activation of inflammasomes and pyroptotic cell deathduring ZIKV infection might be a potential host defencestrategy to amplify the immune response.Traumatic nerv
49、ous system injuriesTraumatic neurological injuries lead to a wide range tolong-termdisabilitiesand/ordeath,associatedwithTable 1 Inflammasome activation in neurological diseases(acute and chronic)DiseaseInflammasomeInducerCell typeReferencesIschaemic strokeNLRP1/ATPH+ionsNeuronsAbulafia et al.,2009;
50、Fann et al.,2013aNLRP3Haemorrhagic strokeNLRP3ROSMicrogliaXiong and Yang,2015Traumatic brain injuryNLRP1P2X7R signallingNeuronsde Rivero Vaccari et al.,2008;Liuet al.,2013aNLRC4AIM2Spinal cord injuryNLRP3P2X4/7R signallingMicroglia,neuronsde Rivero Vaccari et al.,2012NLRP1Bacterial meningitisNLRP3Ca
