Innate Inflammation and Stroke

164 Pages·2010·3.867 MB·English

by  Wolfgang Eisert, Gregory J. del Zoppo, Philip B. Gorelick

Ann.N.Y.Acad.Sci.ISSN0077-8923
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue:InnateInflammationandStroke
Introduction to innate inflammation: the common
denominator of risk factors leading to stroke and TIA
Ihavebeengiventhedifficulttaskoftryingtopresentaclinician’sreactiontothebasicscienceand
clinicallyorientedpresentationsinthissymposium.Iwillnotcommentonthetechnicalaspects
of the basic science—it would be improper for me to do so. Instead I will attempt to extract
a broad view of the extensive and very diverse information discussed—that is, characterize the
forestfromthetrees.
Threeanalogiesoccurtome.
(1) New York City, the location of this meeting. The epidemiological data indicate striking
variations in traditional atherosclerotic risk factors (hypertension, dyslipidemia, diabetes,
metabolicsyndrome,obesity,inactivity,andsmoking),genedistributionthataffectsthese
riskfactors,andthepresenceandextentofinflammationandinflammatorymarkers.The
basicsciencestudiesalsoshowaremarkablevariability,dependingonthefactorsstudiedand
theexperimentalprotocols.Sohowshouldaclinicianconcludewhatfactorsareimportant
in an individual patient? In any geographical region, for example, New York, that would
depend whether one studied, for instance, Chinatown, the Bronx, the Bowery, the Lower
East Side, or Brooklyn. The diversities impress me more than the similarities, so that so-
calledpersonalizedmedicine characterizationofrisks andmarkersshouldbeemphasized
ratherthanlargegroupandpopulation-basedapproaches.
(2) An Agatha Christie mystery. In many of her whodunits, the reader is captivated trying to
identifythemurdererfromthecharactersthataredescribedindetailastheplotproceeds
andthedetectivedoeshissleuthing.However,thereadermaydiscover,intheverylastor
penultimatechapter,thatanewentrant,acousinorfriendofoneofthepreviouslydescribed
characters,wastheculprit,muchtothefrustrationofthereader.Thestorylineissimilar
withregardtogenetics,andinflammatoryandatheroscleroticriskfactors.Newersubstances,
genes, and markers are discovered annually. Often these new entities are more specific or
morepowerful,ormorerepresentativethantheolderestablishedones.Researchisamoving
target,renderingitproblematictohitchone’sstarontoanysinglepresentfinding.Basicand
clinicalresearchmustcontinuouslyconsiderandintegratenewfindings.Thismakesmuch
of the research findings time related and not finally definitive. Clinicians must keep their
eyesandearswelltunedtothelatestdevelopmentsandviewthesecritically.
(3) The Magus, a novel by John Fowles that I recently reread. Fowles plays many tricks on
readersbyfrequentlyalteringimpressionsofthecharactersandtheirmotivationsandtheir
goodandeviltiters.Similarly,bothclinicalandbasicscienceresultsabouttherelevanceand
importanceofvariousmarkers,genes,andfindingsvaryconsiderably.Oftenthisdepends
on quantification, for example, too little and too much alcohol intake is not good, and
sometimesthisdependsontheanimalorsex,age,orethniccharacterizationoftheindividual
orpopulationstudied.SomestudiesfindputativefactorXtobeveryimportant,andthese
findingsarehypedinthemedia,onlyforclinicianstofindthatanotherstudyrepudiatedthe
doi:10.1111/j.1749-6632.2010.05727.x
Ann.N.Y.Acad.Sci.1207(2010)vii–viii(cid:2)c 2010NewYorkAcademyofSciences. vii
Introduction Caplan
findingsofthepriorstudies.FactorY:forexample,cheesemaybetargetedascontributingto
hyperlipidemiaandthedevelopmentofatheroscleroticplaques,andyet,later,newevidence
shows that cheese intake promotes healthy results. At times agents predicted from basic
◦
researchtohavegreatpromisearefoundintrialstobeineffectiveorevenharmful—a180
turnaround. An example is the Enlimomab stroke trial discussed by Gregory del Zoppo.
Use of a humanized murine anti-ICAM-1 antibody to inhibit endothelial cell ICAM-1–
mediated adhesion of polymorphonuclear leukocytes was posited from basic research to
reducethedevelopmentofstroke.Inthistrialthetreatmentwasactuallyharmful,andthe
placebo-treatedpatientgroupactuallydidbetterthanthosetreatedwiththeantibody.
Clinicians must be very wary of first impressions and hypotheses generated by laboratory
andanimalresearch.Positedtreatmentsmustbetestedthoroughlyandindifferentgroupsand
differentsituations.Thingsarenotalwayswhattheyfirstseem.Asinthissymposium,frequent
andintensecommunicationamongclinicians,epidemiologists,andbasicresearchersmustgoon,
andeachgroupmustlisten,butcritically,totheothersifprogressistobemade.Wearealong
wayfromunderstandingthecomplexentitiesofinflammationandatherosclerosisandeonsaway
fromoptimalpreventionandtreatment.
LouisR.Caplan
HarvardMedicalSchool
Boston,Massachusetts
[email protected]
viii Ann.N.Y.Acad.Sci.1207(2010)vii–viii(cid:2)c 2010NewYorkAcademyofSciences.
Ann.N.Y.Acad.Sci.ISSN0077-8923
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue:InnateInflammationandStroke
How inflammation modulates central nervous system
vessel activation and provides targets for intervention—
a personal perspective
JohnHallenbeck
NationalInstituteofNeurologicalDisordersandStroke,NationalInstitutesofHealth,Bethesda,Maryland
Addressforcorrespondence:JohnHallenbeck,M.D.,NationalInstituteofNeurologicalDisordersandStroke,National
InstitutesofHealth,10CenterDriveMSC1401,Building10/Room5B02,Bethesda,[email protected]
Iheredescribealineofresearchthatgrewoutofstudiesofspinalcord–damagingdecompressionsickness,focusedon
theblood–endothelialinterface,thatwasinfluencedbythelocalShwartzmanphenomenon,addressedinnateimmune
andinflammatorymechanisms,andultimatelyarrivedatmucosaltoleranceapproachestopreventstroke.Intranasal
instillationofE-selectinisunderdevelopmentasanovelmeansoftargetingimmunomodulationtoactivatingblood
vesselswithinthevasculartreesupplyingthebrain.Thegoalofthisformoffocusedimmunomodulationistoprevent
recurrentstrokesinpatientsthathavepreviouslysufferedtransientischemicattacksorstrokes.
Keywords: tolerance;stroke;cytokines;immunomodulation;endothelium;E-selectin
IbeganmyresearchcareerasaBerryPlandrafteeat responsesinadditiontothedirecteffectsoflocalen-
theNavalMedicalResearchInstitute,NationalNaval ergyfailureandmembranefailure.Itseemedhighly
Medical Center in Bethesda Maryland in 1971, af- possiblethatthebloodflowingthroughanischemic
ter having completed a neurology residency at the injuryzonecouldbecomeactivatedbythedamaged
University of Michigan. My entrance into stroke or stressed tissue resembling in a general way the
research was somewhat unconventional in that I activationofbloodbybubblesorotherforeignsur-
moved from studies of spinal cord damage in de- faces.Furtherexaminationofthispossibilityledto
compression sickness to an abiding interest in the theconceptof“blood-damagedtissueinteraction,”
mechanisms that induce brain damage in strokes. aforerunnerofreperfusioninjurythatleadstopro-
Amajormechanismunderlyingthepredilectionfor gressiveimpairmentofmicrovascularperfusion.4,5
spinalcorddamageincentralnervoussystem(CNS) Anintriguingmodeloffocalbloodvesselactiva-
decompressionsicknessturnedouttobetheaccu- tionisthelocalizedShwartzmanreactionthatwas
mulation of bubbles and activated blood products first described by Gregory Shwartzman in 1928.6
in the epidural vertebral venous system (Batson’s There is a preparatory step in which endotoxin
Plexus), ultimately leading to venous obstruction, acting as a danger-associated molecular pattern
compromisedtransportofnitrogenoutofthelipid- (DAMP) is injected intradermally where it acts
richspinalcord,andlocalnucleationofgasbubbles through toll-like receptors7 to release proinflam-
inthecord.1,2Animportantfactorintheactivation matorycytokinesandlocallyactivatebloodvessels
ofbloodandlocalbloodvesselsinthevenousplexus in the skin. This will lead to some local erythema
was the 40–100 A˚ zone of electrokinetic forces at thatsubsidesintheabsenceofanyfurtherstimula-
bubble–bloodinterfaces(Lee&Hairston)thatacti- tion.If,however,thereisaprovocativestep,acriti-
vatedthecontactactivationsystemincludingcoagu- callytimedactivationofthecoagulationsystembya
lation,fibrinolysis,complement,kinins,etc.3Given smallnontoxicdoseofendotoxinadministeredin-
this background, I viewed stroke from the start as travenously18–24hafterthepreparatorystep,areas
a process in which blood and tissue responses to ofpetechialhemorrhageappearinthepreparedskin
ischemic stress were likely to be extremely multi- andtheseenlargeandcoalesceintoanareaofhem-
factorialandtoincludeinflammatoryandimmune orrhagicnecrosisthatapproachesthesizeofasilver
doi:10.1111/j.1749-6632.2010.05785.x
Ann.N.Y.Acad.Sci.1207(2010)1–7(cid:2)c 2010NewYorkAcademyofSciences. 1
CNSvesselactivationfocus—personalperspective Hallenbeck
positivemacrophageswereincreasedinratswiththe
strokeriskfactor,hypertension(e.g.,spontaneously
hypertensive rats [SHR] and stroke-prone sponta-
neously hypertensive rats [SHR-SP]) compared to
normotensive controls (e.g., Wistar Kyoto [WKY]
rats).10 In addition, in vitro carotid ring produc-
tionoftumornecrosisfactor(TNF)-(cid:2)inresponse
toarangeofendotoxindoseswaselevatedinSHR
versusWKYrats.11 Weinferredfromthesestudies
thatstrokeriskfactorsactedtoaugmentbloodves-
selactivationwithinthecerebrovascularcirculatory
network.
RosenbergandAirdconductedstudiesofthedif-
ferencesinthemolecularmechanismsthatprovide
Figure 1. Responsestosingle1.8mg/kgintracisternaldoses
ofendotoxinarecomparedfromgroupsofratswithandwith- the primary regulation of hemostasis in vascular
outstrokeriskfactors.Foreachgroup,nisSprague-Dawleyrats bedsofdifferentorgansandalsonotedthatavari-
(SD)37,SDdiabetic(SDDIB)26,SD24-monthsold(SD2Y)13, etyofdifferentsystemiccoagulationdisorderssuch
spontaneouslyhypertensiverats(SHR)26,stroke-pronespon-
asproteinCdeficiency,heparin-bindingsiteofan-
taneouslyhypertensiverats(SHR-SP)4,SHRretiredbreeder
tithrombin III mutation, factor V Leiden variant,
rats(SHR-RB)4,andWistarrats(W)7.
andprothrombinG20210Amutationleadtoorgan-
specificthrombosisratherthanadiffusethrombotic
dollar.8 Our group wondered whether established diathesis with disseminated intravascular coagula-
risk factors for stroke could act locally to prepare tion. They concluded that hemostatic potential is
blood vessels in the brain for a modified Shwartz- not regulated by a synchronous, systemic mech-
man reaction in response to a provocative inflam- anism but is instead controlled asynchronously
matory stimulus such as intracisternally or intra- segmentbysegmentwithinthevasculartreeofan
venouslyinjectedendotoxin.Strokeriskfactorssuch organ.12–14Thelocalendotheliumofavascularseg-
as hypertension, diabetes, advanced age, and ge- ment was viewed as integrating signals that come
neticpredispositiontostrokewerefoundsufficient fromtheblood,thebloodvesselwall,andthesur-
to prepare rat brainstem tissues such that a single roundingparenchymaltissue;inresponsetothison-
intracisternalorintravenousinjectionofendotoxin goingendothelialintegrationofsignalsthatinclude
provokedthereaction,andaffectedrats-manifested cytokines, mechanical forces, circulating lipopro-
neurologic deficits accompanied by pathologic le- teins,coagulationfactors,componentsoftheextra-
sions (Fig. 1). Brain infarcts developed in only a cellular matrix, and DAMPs, the properties of the
small proportion of rats without recognized risk luminal endothelium within a given segment can
factors after endotoxin injection.9 This work sug- cyclefromanantiinflammatoryandanticoagulant
gestedthatoneroleofstrokeriskfactorsistoprime phenotypeatoneextremetoaproinflammatoryand
vesselactivationandendothelialdysfunctionasoc- procoagulantphenotypeattheotherextreme.Such
cursintheShwartzmanreaction,butthatasecond cycling occurs innocuously in normal individuals,
systemic activation of inflammation and coagula- butifthehemostaticpotentialinavascularsegment
tion was necessary to precipitate local thrombosis risesabovesomehomeostaticthresholdascanoccur
orhemorrhageandcauseastroke,namely,a“two- in the presence of stroke risk factors, local throm-
hitphenomenon.” bosisorvesseldamagewithhemorrhagebecomesa
Weexaminedthispossibilityfurtherwithaseries threat.
ofstudiesthatcomparedthenumbersofperivascu- Our studies of the patterns of immunoreactive
larmacrophagesinbrainvesselsandtheendotoxin- TNF-(cid:2) (proinflammatory, prothrombotic), heme
induced levels of secreted proinflammatory cy- oxygenase-1 (HO-1, oxidative stress marker), and
tokinesfromisolatedcarotidringsamonganimals manganesesuperoxidedismutase(MnSOD,antiox-
withriskfactorsforstrokeandthosewithoutsuch idant) around the brain vessels of rats with and
risk factors. The numbers of perivascular ED2- withoutriskfactorsforstrokeprovidesomesupport
2 Ann.N.Y.Acad.Sci.1207(2010)1–7(cid:2)c 2010NewYorkAcademyofSciences.
Hallenbeck CNSvesselactivationfocus—personalperspective
phenotype and express tissue factor, IL-1, TNF-(cid:2),
coagulationfactorbinding/activation,adhesionre-
ceptors,plasminogenactivatorinhibitor-1,platelet
activatingfactor,endothelin,chemokines,andvon
Willebrandfactor.17
Onecouldeasilydichotomizethemolecularpro-
cesses that regulate the phenotype of the luminal
endotheliumintoasubsetthatispotentiallyharm-
ful, the procoagulant and proinflammatory medi-
ators, and a subset that is potentially salutary, the
anticoagulantandanti-inflammatorymediators.It
turnsoutnottobethatsimple.18Forinstance,TNF-
Figure2. Patternsofmanganesesuperoxidedismutase(Mn- (cid:2) would seem to be an archetypal “bad guy” that
SOD) expression around brain vessels of spontaneously hy-
induces both inflammation and cytotoxicity. This
pertensive stroke-prone rats. These patterns were coincident
with the expression patterns of immunoreactive TNF-(cid:2) and cytokine, however, can be harmful19–22 or bene-
hemoxygenase-1inserialsections.Theconcentricringsofim- ficial23,24 or act as a preconditioning stimulus to
munoractiveMnSODappeartoexpandradiallyfromscattered induce stress tolerance25–28 depending on the cir-
vessel epicenters out into the brain parenchyma in a non- cumstances. Indeed, an examination of TNF-(cid:2)
synchronousmanner.Theconcentriccirclessuggestthatthese
function within the conventional “ischemic cas-
responsesoccurinwavesofactivationanddeactivationofindi-
cade” can provide a semi-quantitative insight into
vidualvascularsegments.
the complexity and multifactorality of the regula-
tory network in cells. A widely accepted series of
for the dynamic segmental control model of generalpathobiologicalmechanismsthataresetinto
hemostasis described above.15 Within brain sec- motionbybrainischemiawouldincludemetabolic
tions from rats without stroke risk factors, cross- failure,membranefailure,excitotoxicity,apoptosis,
sectionedvesselsexhibitedscatteredcoincidentvas- oxidative/nitrativestress,pathologicalgeneexpres-
cular and perivascular halos of immunoreactive sion, neurovascular unit dysfunction, and inflam-
TNF-(cid:2),HO-1,andMnSODthatappearedtoperi- matory/immune responses.29 Cytokines constitute
odicallybeginasthinringsoutliningandhighlight- onlyonesubsetoftheinflammatory/immuneme-
ing a vessel then expanding centrifugally into the diators and there are over 100 of these signaling
surroundingparenchymabeforefading.Repeating molecules. Drilling down further, one of these cy-
cyclesoftheexpandingimmunoreactivityofthese tokines is TNF-(cid:2), which reacts with two different
regulatorymoleculeswereclearlyvesselcentricand receptors.Astudymappingtheproteininteraction
werelikelytohavebeenresponsestocyclicactiva- networkthatlinksTNF-(cid:2)receptoractivationwith
tionandinactivationofdiscretevascularsegments activationofonlyoneofitstranscriptionfactortar-
because the number and intensity of the perivas- gets, nuclear factor (cid:3)B (NF(cid:3)B), showed that there
cular rings was significantly increased in rats with are221protein–proteininteractionsthatmodulate
stroke risk factors and in risk factor-free rats that NF(cid:3)B activation.30 Once activated, NF(cid:3)B can in-
receivedintravenousendotoxin(Fig.2). fluence the expression of more than 150 genes.31
Mediatorsoftheanticoagulant/antiinflammatory Bygoingthroughthementalexerciseofscalingthis
phenotype of the luminal endothelium in a vas- levelofcomplexitybackthroughotherrecognized
cular segment can include prostacyclin, nitric strokepathobiologicalmechanisms,onecangaina
oxide, heparin-like glycosaminoglycans, throm- greaterappreciationoftheextraordinarycomplex-
bomodulin, protein C, protein S, tissue-type ityandmultifactoralityofthedynamicnetworkthat
plasminogen activator, tissue factor pathway in- controlsthecellularresponsesrelatedtoischemia.
hibitor, hemoxygenase-1, MnSOD, and adeno- In the mid-1990s, Kyra Becker, an outstand-
sinediphosphatase/5(cid:3)-nucleotidase.16Inresponseto ing postdoctoral fellow with a strong interest
proinflammatorymediatorslikeTNF-(cid:2),interleukin in immunology, joined our group. She decided
(IL)-1, and lipopolysaccharide (LPS), luminal en- to address the stroke cytoprotection problem by
dothelium can make a “Jekyll to Hyde” change in augmenting endogenous immune regulatory
Ann.N.Y.Acad.Sci.1207(2010)1–7(cid:2)c 2010NewYorkAcademyofSciences. 3
CNSvesselactivationfocus—personalperspective Hallenbeck
ensemblesthatfunctionbroadlywithinthedynamic E-selectin polypeptide that included much of the
network rather than by identifying and targeting extramembranousportionthatleukocytereceptor.
asingleinflammatoryorimmunemechanismthat E-selectinexpressionisvirtuallyconfinedtoluminal
wouldhavearelativelycircumscribednetworkfunc- endotheliumanditisnotconstitutivelyexpressed.
tion. Specifically, she proposed to apply to studies Itisonlyexpressedinvesselsegmentsthatarebe-
of brain ischemia the mucosal tolerance model32 coming activated. We were struck (a) because lo-
that was known to modulate immune responses calreleaseofimmuneandinflammatorymediators
and had shown efficacy in experimental autoim- contributestolocalvesselactivation,appropriately
muneencephalitismodels.Inthemucosaltolerance targeted local immunomodulation could counter
model,serialtransmucosaladministration of“low thatactivationand(b)becauseT-lymphocytesare
dose”antigeninthemicrogramrangewilleitheren- key players in the regulation of the immune sys-
countergut-associatedlymphoidtissueifdelivered tem, induction of mucosal tolerance to E-selectin
orallyorwillencounternasal-associatedlymphoid could potentially serve to target regulatory T cells
tissue if instilled intranasally. CD4+ lymphocytes to activating blood vessel segments, provide local
canbeprimedbyantigenpresentingcells(APCs)to immunomodulation,andreducetheriskofstroke
differentiateintoregulatoryTcellsthatwilltraffic inindividualswithstrokeriskfactors.
through the body and secrete IL-10 (Tr1 cells) or Our initial study was in spontaneously hyper-
TGF(cid:4) (Th3 cells) when the antigen to which they tensive, stroke-prone rats (SHRSP/Izm) that had
have been primed is again presented to them by been kindly supplied by Y. Yamori from the Dis-
APCs. If the priming antigen can be presented ei- ease Model Cooperative Research Association to
therlocallyorwithindraininglymphnodes(from MariaSpatzinconsiderationofhermanyyearsas
whichtheregulatoryTcellscanreturntothelocusof a mentor for Japanese visiting fellows at the NIH.
inflammation),theseregulatoryTcellscanrelease After initial dose–response studies we instilled in
immunomodulatorycytokinesandlocallysuppress thenonboostergroup,5mgofrecombinanthuman
inflammationandimmuneresponsesregardlessof E-selectin(rhES)intranasallyonaneveryotherday
whether or not the presented antigen is actually scheduleforfivedosesandthenfollowedtheanimals
causing the inflammation. This process is termed untiltheydevelopedstrokes,othercomplicationsof
“bystander suppression.” A brain antigen, myelin severe hypertension such as heart failure or renal
basicprotein(MBP)wasfedbygavagetorats,and failure,oruntilcompletionofthe56-weekstudy.We
theanimalsweresubsequentlyprotectedfromtran- alsogaverepeatedfive-doseschedulesofE-selectin
sient middle cerebral artery occlusion-induced is- intranasally at 21-day intervals to a booster group
chemicbraindamagecomparedtoratsfedanonspe- of animals and followed them as described above.
cific,nonmammalianprotein,ovalbumin.Inaddi- Control animals received single or booster sched-
tion,MBPsensitizationinanotheranimalgroupled ules of intranasal instillation of either phosphate
toincreasedischemicbraindamage.Furtherstud- bufferedsaline(PBS)oranonmammalianprotein,
iesthatincludeddemonstrationofantigen-specific ovalbumin,andalsohadcorrespondingfollow-ups.
suppression of delayed-type hypersensitivity vali- Incomparisontotheothergroups,theanimalsthat
dated the presence of an antigen-specific state of receivedboosterinstillationsofrhESshowedamas-
immune tolerance.33 This work showed that en- sivelyreducedincidenceofischemicstrokeandthe
dogenous immunomodulation mechanisms could absenceofparenchymalhemorrhages34(Fig.3).
be harnessed to change immune network dynam- On the basis of this study, we began to further
ics in acute stroke in order to suppress brain cell develop intranasal instillation of E-selectin for the
damage. secondarypreventionofstroke.Wereasonedthatif
A limiting factor in the application of this ap- a stroke-preventive agent that is already on board
proachtoacutestroketreatmentisthattheinduc- had some cytoprotective capacity, it would confer
tionofmucosaltolerancebyserialexposureofanti- added value because the earlier a therapeutic can
gens to a mucosal surface such as the gut or the be administered aftera stroke, thehigher the like-
nasalmucosatakesseveraldaystodevelop.Webe- lihood of a beneficial response. We therefore per-
came aware in the late 1990s that Protein Design formedpermanentmiddlecerebralarteryocclusion
Laboratories had produced a recombinant human (MCAO) studies in SHR-SP rats and found that
4 Ann.N.Y.Acad.Sci.1207(2010)1–7(cid:2)c 2010NewYorkAcademyofSciences.
Hallenbeck CNSvesselactivationfocus—personalperspective
Figure 3. Comparisonsareshownoftheaveragenumberofbraininfarctsperanimal(A),theaverageareaofbraininfarcts
per animal (B), the average number of brain intraparenchymal hemorrhages per animal (C), and the average area of brain
intraparenchymalhemorrhagesperanimal(D)ineachof4experimentalgroups.Theexperimentalgroupsreceivedeitherasingle
scheduleoffiveeveryotherday5(cid:3)gdosesofintranasallyinstilledovalbumenorE-selectin,ortheyreceivedboosterrepetitionof
thesedosagescheduleseverythreeweekstomaintainanymucosaltolerancethathadbeeninduced.
E-selectintolerizationstronglyreducedinfarctvol- Inourcurrentworkonthisproject,wearecar-
umescomparedtoPBScontrols.35 Inaddition,we rying out the necessary bridging studies to show
replicatedthisfindingbyadoptivetransferofspleen equivalencebetweenhomologousratormurineE-
cells from E-selectin tolerized donor animals into selectin antigen in rodents and heterologous hu-
naive SHR-SP showing that E-selectin tolerization manE-selectininrodents.Wearealsoconducting
isacell-mediatedphenomenon. safetyanddosestudiesthatexaminebothintended
We have also shown the efficacy of mucosal to- biological/immunomodulatory responses and po-
lerization to E-selectin in reducing white matter tentialtoxicity/immunotoxicityconsequencesofex-
damageandfunctional/behavioraldeficitsinmod- tended periods of E-selectin nasal instillation. An
elsofvascularcognitiveimpairment,36inaugment- additional goal is to validate techniques that can
ingadultneurogenesisandimprovingfunctionalre- be applied in our future clinical trials to provide
covery after stroke,37 in suppressing subarachnoid accessiblebiomarkersoffunctionalactivityandim-
hemorrhage-delayedvasospasm,38 and(inunpub- munotoxicity. This workwillleadinto nonhuman
lished work) in improving neurological outcome primatestudiesthatposethatthefinalhurdlebefore
in an experimental autoimmune encephalomyeli- filinganINDandconductingaPhaseIclinicaltrial.
tis model of multiple sclerosis, and in reducing of We hope to immunomodulate the intricately
aorticplaqueburdeninamodelofatherosclerosis interconnected ensembles of molecular mecha-
inapolipoproteinE(ApoE)-nullmice.Thesestud- nisms in the dynamic network that function in a
ieshaveinvolveddifferentsetsofinvestigatorsand stroke-prone individual and can lead to a stroke.
havebeenconductedinseveraldifferentlabs. We have chosen an approach that has relatively
Ann.N.Y.Acad.Sci.1207(2010)1–7(cid:2)c 2010NewYorkAcademyofSciences. 5
CNSvesselactivationfocus—personalperspective Hallenbeck
plurifunctional effects in the network and is con- 12. Aird,W.C.2005.Spatialandtemporaldynamicsoftheen-
sonant with a prescient quote from Oscar Ratnoff dothelium.J.Thromb.Haemost.3:1392–1406.
(who identified Factor XII Hageman factor) that 13. Edelberg,J.M.,P.D.Christie&R.D.Rosenberg.2001.Regu-
lationofvascularbed-specificprothromboticpotential.Circ.
influencedmegreatlyearlyinmycareer.Inacom-
Res.89:117–124.
prehensive review that integrated hemostasis, fib-
14. Rosenberg,R.D.&W.C.Aird.1999.Vascular-bed-specific
rinolysis, immunity, and inflammation,39 he con- hemostasisandhypercoagulablestates.N.Engl.J.Med.340:
cludedhisarticlewiththeinsightthatinvestigators 1555–1564.
interestedinanygivensystem(e.g.,complementor 15. Ruetzler,C.A.etal.2001.Brainvesselsnormallyundergo
cyclic activation and inactivation: evidence from tumor
kinins)tendtobreakthesystemoutandstudyitin
necrosisfactor-alpha,hemeoxygenase-1,andmanganesesu-
isolation,asifitoperatedinadiscreteanddisartic-
peroxidedismutaseimmunostainingofvesselsandperivas-
ulatedfashion.Inthebody,however,thesesystems cularbraincells.J.Cereb.BloodFlowMetab.21:244–252.
areintricatelyinterconnectedand,inRatnoff’svivid 16. Hallenbeck,J.M.1996.Inflammatoryreactionsattheblood–
phrase,“formaseamlessweb.”Thisisbothabeau- endothelialinterfaceinacutestroke.Adv.Neurol.71:281–
297;discussion297–300.
tiful and a useful concept for those interested in
17. Goldberg,R.B.2009.Cytokineandcytokine-likeinflamma-
improvingthepreventionandtreatmentofstroke.
tionmarkers,endothelialdysfunction,andimbalancedco-
agulationindevelopmentofdiabetesanditscomplications.
Conflictsofinterest
J.Clin.Endocrinol.Metab.94:3171–3182.
18. Hallenbeck,J.M.2002.Themanyfacesoftumornecrosis
J.H. has a patent on the use of E-selectin for im-
factorinstroke.Nat.Med.8:1363–1368.
munomodulating vessel activation and preventing
19. Barone, F.C. et al. 1997. Tumor necrosis factor-alpha.
stroke. Amediatoroffocalischemicbraininjury.Stroke28:1233–
1244.
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Ann.N.Y.Acad.Sci.1207(2010)1–7(cid:2)c 2010NewYorkAcademyofSciences. 7
Ann.N.Y.Acad.Sci.ISSN0077-8923
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue:InnateInflammationandStroke
Innate inflammation as the common pathway of risk
factors leading to TIAs and stroke
GregoryJ.delZoppo1,2 andPhilipB.Gorelick3
1DivisionofHematology,DepartmentofMedicine,and2DepartmentofNeurology,UniversityofWashingtonSchoolof
Medicine,Seattle,Washington.3DepartmentofNeurologyandRehabilitation,UniversityofIllinoisCollegeofMedicineat
Chicago,Chicago,Illinois
Addressforcorrespondence:Prof.GregoryJ.delZoppo,DivisionofHematology,DepartmentofMedicine,Universityof
WashingtonSchoolofMedicine,Box359756atHarborviewMedicalCenter,325NinthAvenue,Seattle,WA98104.
[email protected]
Intheearlymomentsofischemicstroke,theprocessesofthrombosis,ischemia,andinflammationareintimately
interrelated,settinginmotionaninjurythatleadstoinfarctionandpermanentdamage.Ofthese,thepotentialroles
thatinnateinflammationcanplayintheevolutionofbraintissuedamageinresponsetotheischemicinjuryarenot
wellunderstood.Observationsinthesettingsofatheroscleroticcardiovasculardiseaseandcerebralischemiahave
muchtoteacheachother.Thefollowingprovidesanintroductoryoverviewoftheconference“InnateInflammation
astheCommonPathwayofRiskFactorsLeadingtoTransientIschemicAttacksandStroke:Pathophysiologyand
Potential Interventions,” which took place May 9–10, 2010 at the New York Academy of Sciences. This meeting
wasconvenedtoexploreaspectsofthecellularandtissueresponsestoinnateinflammation.Afacultyofleading
expertswasassembledtodiscusstheroleofinflammationinlaboratorymodelsofstrokeandmyocardialinfarction,
definepossiblenovelmeansfromlaboratoryevidencetoalleviateorpreventinflammationunderlyingstrokeand
cardiovasculardisease,andpresentinformationoncurrentexamplesofclinicaltranslationoftheseunderstandings
inrelationtohumanstrokeandmyocardialinfarction.
Keywords: neurovascularunit;innateinflammation;infection;stroke;cognitiveimpairment/Alzheimer’sdisease
Occlusion of a brain-supplying artery initiates a clear.Toexplaintheobservationthatprotectionof
complextime-dependentseriesofeventsthatevolve neurons alone, demonstrated experimentally, has
intopermanentstructuralinjuryintheterritoryat- been inadequate to lead to functional benefit in
riskandleadtotheclinicalsignsofischemicstroke. clinicalstroke,aconceptualshifthasoccurred.The
Bothexperimentalandclinicaltrialworksofthelast “neurovascularunit”isaconceptualframeworkthat
30 years have shown that recanalization of an oc- linksmicrovesselandneuronfunction,andtheirre-
cludedarterywithinhoursoftheonsetofischemia sponsestoinjury.Italsorepresentsastructuralar-
can limit the volume of permanent injury, de- rangementthatlinksmicrovesselcomponentswith
pendinguponthelocationofthevascularterritory neuronsviatheircommonastrocytes.1,2Itassumes
involved.Theevolutionofischemicinjurytotheul- thatthefunctionofthe“unit”canbemodifiedor
timateinfarctioninvolvestheactivationofinflam- regulated by other cells associated with the unit.
matory processes. Injury to the microvasculature Componentsoftheneurovascularunitincludethe
without overt clinically detectable focal ischemia endothelium,astrocytesandtheirend-feet,theex-
canproducemoresubtlebraininjurythatalsoin- tracellular matrix between these cell components,
volvesinflammatorypathways.Hence,thrombosis, pericytes, neurons and axons, and other cells that
ischemia,andinflammationareinterrelatedincen- can modulate the function, including microglia,
tralnervoussystem(CNS)injury. oligodendroglia,mastcells,andperhapsothercells
Theimportanceofmicrovesselintegrityfornor- fromothersources.2,3
malbrainfunctionandforlimitingthefunctional Each of these cell types can respond with a
disturbances of neurons during ischemia is now repertoire of signals, receptors, and cell function
doi:10.1111/j.1749-6632.2010.05762.x
8 Ann.N.Y.Acad.Sci.1207(2010)8–10(cid:2)c 2010NewYorkAcademyofSciences.