Alle x perimentalprotocolswereapprovedbyt heVictoriaUniversit yofWellingtonAnimalEthicsCommittee(Permit2014R17M)and performedaccordingtoInstitutionalguidelines.
aUThOrcOnTriBUTiOns
CPcarriedoutexperiments,analyzedthedataandwrotethemanusc
ript.S-CTgeneratedNbstocksandcarriedo utexperiments.ASandJDdes igned,o ptimized,andanalyzedconfocalmicroscopyexperiments .RWandOLcarriedo
utRT-qPCRtimecourses.CRp rovidedessentialr eagentsandexperime ntaladvice.LCprovidedconceptualinsightsanddataonthemodel.
GLGandFRprovidedconceptualinsightsandFRsupervisedthepr oject.AllAuthorsprovidedfeedbackonthemanuscript.
acKnOWleDgMenTs
Theauthorswishtothanktheex pertsupportoftheMalaghanInstitut eofMedicalResearchHughGreenCytometryCore,ResearchInfor mationTechnologiesandBiomedicalR esearchUnitstaff.Weareex tremelygratefultoProfessorShizuoAkira,OsakaUniversity,fordo /11/B/NZ3/00189toJD.Thisworkwasmadepossiblebyt heg rac iousg iftofa F V 1 2 0 0 c onfocalm i c roscopebyt heInfinityFounda tion,NewZealand.
1. WalshK P,MillsK HG.D endriticc ellsandotheri n nated e terminantsofThelp ercellpolarisation.TrendsImmunol(2013)34:521–
30.doi:10.1016/j.it.2013.07.006
2. FitzsimmonsC M , FalconeF H , D unneDW.Helmintha llergens,p arasite-specificIgE,anditsprotectiveroleinhumanimmunity.FrontImmunol(2014)5:61.
d oi:10.3389/fimmu.2014.00061
3. PalmNW,RosensteinRK,MedzhitovR.Allergichostdefences.Nature(2012)484:
465–72.doi:10.1038/nature11047 4.
Méndez-SamperioP.MoleculareventsbywhichdendriticcellspromoteTh2immuneprote ctioninhelmithinfection.InfectDis(Auckl)(2016)4235:1–
6.doi:10.1080/23744235.2016.1194529
5. VannellaKM, RamalingamTR,BorthwickLA,BarronL, HartK M, Thompson RW,etal.CombinatorialtargetingofTSLP,IL-25,andIL-33intype2cytokine–
driveninflammationandfibrosis.SciTranslMed(2016)8:1–
13.d oi:10.1126/scitranslmed.aaf1938
6. EisenbarthSC,PiggottDA,HuleattJW,VisintinI,HerrickCA,BottomlyK.Lipop
olysaccharide-enhanced,toll-likereceptor4-dependentThelpercellt ype2 responsestoi n haledantigen.J ExpMed( 2 0 0 2 ) 1 9 6 : 1 6 4 5 – 5 1 . doi:10.1084/jem.20021340
7. ThomasPG,CarterMR,AtochinaO,Da’DaraAA,PiskorskaD,McGuireE,etal.
Maturationofdendriticcell2phenotypebyahelminthglycanusesa
toll-likereceptor4-dependentmechanism.JImmunol(2003)171:5837–
41.doi:10.4049/jimmunol.171.11.5837
8. PullanRL,SmithJL,JasrasariaR,BrookerSJ.Globalnumbersofinfectionanddisea seburdenofsoiltransmittedhelminthinfectionsin2010.ParasitVectors(2014)7 : 3 7 . d oi:10.1186/1756-3305-7-37
9.
Wills-KarpM , S antelizJ,KarpC L . T hegermlesst heoryofa llergicd isease:revisitingthe hygienehypothesis.NatRevImmunol(2001)1:69–75. doi:10.1038/35095579 10. TheWorldAllergyOrganisation.In:PawankarR,CanonicaGW,HolgateST,Loc
keyRF,BlaissMS.TheWhiteBookonAllergy:Update2013.TheWorldAllergyO rganizationJournal.(2014).7p.
11. ConnorL M , TangS C , CognardE , O chiaiS , HilliganK L , OldSI,e t a l.T h 2 respon sesareprimedbyskind endriticc ellswithd istinctt ranscriptionalprofiles.JExpMed(
2017)214:125–42.doi:10.1084/jem.20160470
12. WebbLM,LundieRJ,BorgerJG,BrownSL,ConnorLM,CartwrightAN,etal.
TypeIinterferonisrequiredforThelper(Th)2inductionbydendriticcells.
EMBOJ ( 2 0 1 7 ) 3 6 ( 1 6 ) : 2 4 0 4 – 1 8 . d oi:10.15252/embj.201695345 13.
LeBonA,ToughDF.TypeIinterferonasastimulusforcross-priming.CytokineGrowthFactorRev(2008)19:33–
40.doi:10.1016/j.cytogfr.2007.10.007
14. IvashkivLB,DonlinLT.RegulationoftypeIinterferonresponses.NatRevImmu nol(2014)14:36–49.doi:10.1038/nri3581
15. CrouseJ,KalinkeU,OxeniusA.RegulationofantiviralTcellresponsesbytypeIi nterferons.NatRevImmunol(2015)15:231–42.doi:10.1038/nri3806
16. GautierG,HumbertM,DeauvieauF,ScuillerM,HiscottJ,BatesEE,etal.
At ypeIinterferonautocrine-paracrineloopisinvolvedi n Toll-likerecep-tor-inducedi
nterleukin-12p70secretionbyd e ndriticc ells.J ExpMed( 2 0 0 5 ) 201:1435–
46.d oi:10.1084/jem.20041964
17. SimmonsDP,WearschPA,CanadayDH,MeyersonHJ,LiuYC,WangY,etal.
TypeIIFNdrivesadistinctivedendriticcellmaturationphenotypethatallowsconti nuedclassIIMHCsynthesisandantigenprocessing.JImmunol(2012)188:3116–
26.d oi:10.4049/jimmunol.1101313
18. PantelA,TeixeiraA,HaddadE,WoodEG,SteinmanRM,LonghiMP.DirecttypeII FNbutnotMDA5/TLR3activationofdendriticcellsisrequiredformaturationan dmetabolicshifttoglycolysisafterpolyICstimulation.PLoSBiol( 2 0 1 4 ) 1 2 ( 1 ) : e 1 0 0 1 7 5 9 . d oi:10.1371/journal.pbio.1001759
19. NagaiT,DevergneO,MuellerTF,PerkinsDL,vanSeventerJM,vanSeventerGA.
TimingofIFN-ex posureduringhumandendriticcellmaturationandnaiveThcellstimulationh
ascontrastingeffectsonTh1subsetgeneration:aroleforIFN-
mediatedregulationofIL-12familycytokinesandIL-18innaiveTh c elld i f ferentiation.J Immunol(2 0 0 3 ) 1 7 1 :5 2 3 3 – 4 3 .d oi:10.4049/jimmunol.171.10.5233
20. HondaK , S a kaguchiS , NakajimaC , WatanabeA , YanaiH , MatsumotoM , eta l.
Selectivec ontributionofI F N
-a lph-a/bet-as i g n-alingtot hem-atur-ationofdendriticc ellsi nducedbyd ouble-strandedR NAorv irali n fection.ProcNatlAcadSciUSA(2003)100:10872–
7.doi:10.1073/pnas.1934678100
21. KaishoT,HoshinoK,IwabeT,TakeuchiO,YasuiT,AkiraS.Endotoxincaninduce
MyD88-deficientdendriticcellstosupportT(h)2celldifferentiation.IntImmunol(2002)14 :695–700.doi:10.1093/intimm/dxf039
22. GehrkeN,MertensC,ZillingerT,WenzelJ,BaldT,ZahnS,etal.Oxidativedamage ofDNAconfersresistancetocytosolicnucleaseTREX1degradationandpotentiat esSTING-dependentimmunesensing.Immunity(2013)39:482–
95.d oi:10.1016/j.immuni.2013.08.004 23.
LoodC,BlancoLP,PurmalekMM,Carmona-RiveraC,DeRavinSS,SmithCK,etal.Neutrophilextracellulartrapsenrichedinoxi dizedmitochon-drialDNAareinterferogenicandcontributetolupus-likedisease.NatMed(2016)2 2 : 1 4 6 – 5 3 . d oi:10.1038/nm.4027 24. Garcia-RomoG S , CaielliS , VegaB,ConnollyJ,A llantazF,XuZ , e t a l.
NettingneutrophilsaremajorinducersoftypeIIFNproductioninpediatricsystem iclupuserythematosus.SciTranslMed(2011)3:73ra20.doi:10.1126/scitranslme d.3001201
25. MarichalT,OhataK,BedoretD,MesnilC,SabatelC,KobiyamaK,etal.DNAreleas edfromdyinghostcellsmediatesaluminumadjuvantactivity.NatMed(2011)1 7 : 9 9 6 – 1 0 0 2 . d oi:10.1038/nm.2403
26. BoucheryT,KyleR,CamberisM,ShepherdA,FilbeyK,SmithA,etal.ILC2sandT c ellsc ooperatetoe nsuremaintenanceofM2 macrophagesforlungimmunityaga insthookworms.NatC ommun( 2 0 1 5 ) 6 : 6 9 7 0 . d oi:10.1038/ncomms797 0
27. PesceJT,LiuZ,HamedH,AlemF,WhitmireJ,LinH,etal.Neutrophilsclearbacteri aassociatedwithparasiticnematodesaugmentingthedevelopmentofaneffective Th2-typeresponse.JImmunol(2008)180:464–
74.doi:10.4049/jimmunol.180.1.464
28. ChenF,WuW,MillmanA,CraftJF,ChenE,PatelN,etal.Neutrophilsprimealong-livedeffectormacrophagephenotypethatmediatesacceleratedhelminthexpulsio n.NatImmunol(2014)15:938–46.doi:10.1038/ni.2984
29. CamberisM,ProutM,TangSC,Forbes-BlomE,RobinsonM,KyleR,etal.
Evaluatingt hei n v ivoT h 2 primingp otentialamongc ommona llergens.
JImmunolMethods(2013)394:62–72.d oi:10.1016/j.jim.2013.05.004 30.
OkanoM,SatoskarAR,NishizakiK,HarnDAJr,Lacto-N-fucopentaoseIIIfoundonSchistosomamansonieggantigensfunctionsasadjuvan tforproteinsbyinducingTh2-typeresponse.JImmunol(2001)167:442–
50.doi:10.4049/jimmunol.167.1.442
31. SwieckiM , WangY,R iboldiE , KimA H , DzutsevA , GilfillanS , e t a l.Celldepletio ninmicethatexpressdiphtheriatoxinreceptorunderthecontrolofSiglecHe ncompas sesmoret hanplasmacytoidd e ndriticc ells.J Immunol(2014)1 9 2 : 4 4 0 9 – 1 6 . d oi:10.4049/jimmunol.1303135
32. TakeuchiO,HoshinoK , KawaiT,S anjoH , TakadaH , O g awaT,e t a l.
DifferentialrolesofTLR2 andTL R4 in recognitionofg ram-
negativeandgram-positivebacterialcellwallcomponents.Immunity(1999 )11:443–
51.doi:10.1016/S1074-7613(00)80119-3
33. WongSL,DemersM,MartinodK,GallantM,WangY,GoldfineAB,etal.
DiabetesprimesneutrophilstoundergoNETosis,whichimpairswoundhealing.Na tMed(2015)21:815–9.doi:10.1038/nm.3887
34. ToussaintM , JacksonDJ,SwiebodaD,GuedánA , TsourouktsoglouT D,Chin gYM,et a l.HostDNAreleasedbyNETosispromotesrhinovirus-in-ducedtype-2allergicasthmaex acerb ation.NatMed(2 01 7 ) 23(6):681–
91.doi:10.1038/nm.4332
35. CharlesN,HardwickD,DaugasE,IlleiGG,RiveraJ.BasophilsandtheThelpe r2environmentcanpromotethedevelopmentoflupusnephritis.NatMed( 201 0) 16 :7 01 –7.d oi:10.1038/nm.2159
36.
SchindelinJ,Arganda- CarrerasI,FriseE,KaynigV,LongairM,PietzschT,etal.Fiji:anopen-sourceplatformforbiological-imageanalysis.NatMethods(2012)9 : 6 7 6 – 8 2 . d oi:10.1038/nmeth.2019
37. SchmidB,SchindelinJ,C ardonaA , LongairM , HeisenbergM . A hi gh-level3DvisualizationAPIforJavaandImageJ.BMCBioinformatics(2010)11:27 4.doi:10.1186/1471-2105-11-274
38. ConnorL M , TangS - C , CamberisM , LeGrosG , R oncheseF.Helminth-
conditioneddendriticcellsprimeCD4+TcellstoIL-4productioninvivo.JImmunol(2014)193(6):2709–
17.doi:10.4049/jimmunol.1400374
39. BranzkN,LubojemskaA,HardisonSE,WangQ,GutierrezMG,BrownGD,etal .Neutrophilssensemicrobesizeandselectivelyreleaseneutrophilextra-cellulartrapsinresponsetolargepathogens.NatImmunol(2014)15:1017–
25.doi:10.1038/ni.2987
40. BranzkN,PapayannopoulosV.MolecularmechanismsregulatingNETosisini nfectionanddisease.SeminImmunopathol(2013)35:513–
30.doi:10.1007/s00281-013-0384-6
41. LeshnerM,WangS,LewisC,ZhengH,ChenXA,SantyL,etal.PAD4medi-atedhistonehypercitrullinationinducesheterochromatindecondensationand
chromatinunfoldingtoformneutrophilextracellulartrap-likestructures.FrontImmunol(2012)3:307.doi:10.3389/fimmu.2012.00307 42. PapayannopoulosV,MetzlerK D,HakkimA , ZychlinskyA .
Neutrophilelas-taseandmyeloperoxidaseregulatet heformationofneutrophile x t racellulartraps.
JCellBiol(2010)191:677–91.doi:10.1083/jcb.201006052
43. BlasiusAL,GiurisatoE,CellaM,SchreiberRD,ShawAS,ColonnaM.Bonemar
rowstromalcellantigen2isaspecificmarkeroftypeIIFN-producingcellsinthenaivemouse,butapromiscuouscellsurfaceantigenfollo wingIFNstimulation.J Immunol( 2 0 0 6 ) 1 7 7 : 3 2 6 0 –
5 . d oi:10.4049/jimmunol.177.5.3260
44. McFarlaneAJ,McSorleyHJ,DavidsonDJ,FitchPM,ErringtonC,MackenzieKJ,
etal.Enterichelminth-inducedtype-Iinterferonsignallingprotectsa gainstpulmonaryvirusi n fectiont hroughi nteracti onwitht hemicrobiota.JAllergyClinImmunol(2017)140(4):1068.e–
78.e.doi:10.1016/j.jaci.2017.01.016
45. HondaK,YanaiH,TakaokaA, TaniguchiT.RegulationofthetypeIIFNindu ction:a currentv iew.IntImmunol( 2 0 0 5 ) 1 7 : 1 3 6 7 –
7 8 . d oi:10.1093/intimm/dxh318 46.
McNabF,Mayer-BarberK,SherA,WackA,O’GarraA.TypeIinterferonsininfectiousdisease.
NatRevImmunol(2015)15:87–103.doi:10.1038/nri3787
47. ToshchakovV,JonesBW,PereraPY,ThomasK,CodyMJ,ZhangS,etal.TLR4,but notT L R 2 , mediatesI F N -
beta-inducedSTAT1alpha/beta-dependentgeneexpressioninmacrophages.NatImmunol(2002)3:392–
8.doi:10.1038/ni774 48.
vanPeschV,LanayaH,RenauldJ-C,MichielsT.Characterizationofthemurinealphai nterferongenef amily.J Virol(
20 04 ) 7 8: 82 19 –2 8. d oi:10.1128/JVI.78.15.8219-8228.2004
49. SwieckiM,ColonnaM.Themultifacetedbiologyofplasmacytoiddendriticcell s.NatRevImmunol(2015)15:471–85.doi:10.1038/nri3865
50. AsselinPaturelC, BrizardG, PinJ
-J,BrièreF,TrinchieriG. Mousestraindifferencesinplasmacytoiddendriticcell frequencyandfunctionrevealedbyanovelmonoclonalantibody.JImmunol(20 03)171:6466–77.doi:10.4049/jimmunol.171.12.6466
51. ClarkSR,MaAC,TavenerSA,McDonaldB,GoodarziZ,KellyMM,etal.
PlateletTLR4activatesneutrophilextracellulartrapstoensnarebacteriainse pticblood.NatMed(2007)13:463–9.doi:10.1038/nm1565
52. YippBG,PetriB,SalinaD,JenneCN,ScottBN,ZbytnuikLD,etal.Infection-inducedN ETosisisa dynamicprocessi nvolvingneutrophilmultitaskinginviv o.NatMed(2012)18:1386–93.doi:10.1038/nm.2847
53. LindauD,MussardJ,RabsteynA,RibonM,KötterI,IgneyA,etal.TLR9indep endentinterferonαproductionbyneutrophilsonNETosisinresponsetoc i rcula tingchromatin,a keylupusautoantigen.AnnR heumD i s( 2 0 1 3 ) 73(12):2199–
207.doi:10.1136/annrheumdis-2012-203041
54. PandaSK,KumarS , TupperwarNC,VaidyaT,GeorgeA , RathS , e t a l.
ChitohexaoseactivatesmacrophagesbyalternatepathwaythroughTLR4andblo cksendotoxemia.PLoSPathog(2012)8:e1002717.doi:10.1371/journal.ppat.
1002717
55. MukherjeeS, KarmakarS,BabuSS.TLR2 andTLR4 mediatedhostimmunerespo nsesinmajorinfectiousdiseases:areview.BrazJInfectDis(2016)20:1–
12.d oi:10.1016/j.bjid.2015.10.011
56. MillienVO,LuW,ShawJ,YuanX , MakG , R obertsL , e t a l.C leavageoffibrinogen byproteinaseselicitsa llergicresponsest
hroughToll-likereceptor4.Science(2013)341:792–6.doi:10.1126/science.1240342 57. Bonne-AnnéeS,KerepesiLA,HessJA,WesolowskiJ,PaumetF,LokJB,etal.
Extracellulart rapsareassociatedw ithhumanandmouseneutrophilandmacroph agemediatedkillingoflarvalStrongyloidesstercoralis.MicrobesInfect(2014)1 6 : 5 0 2 – 1 1 . d oi:10.1016/j.micinf.2014.02.012
58. TrompetteA,DivanovicS,VisintinA,BlanchardC, HegdeRS,MadanR,etal.
Allergenicityresultingfromfunctionalmimicryofatoll-likereceptorcomplexprotein.Nature(2009)457:585–8.doi:10.1038/nature07548 59. TundupS,SrivastavaL,NorbergT,WatfordW,HarnD.Aneoglycoconjugatecont
ainingt hehumanm i lksugarL N F PIIId r ivesanti-inflammatorya cti-vationofantigenpresentingcellsinaCD14dependentpathway.PLoSOne(2015 )10(9):e0137495.doi:10.1371/journal.pone.0137495
60. LonghiMP,TrumpfhellerC,IdoyagaJ,CaskeyM,MatosI,KlugerC,etal.
Dendriticc ellsrequirea s y stemict ypeI i nterferonresponsetomatureandinduceC D4+Th1immunitywithpolyICasadjuvant.JExpMed(2009)206:1589–
602.d oi:10.1084/jem.20090247
61. BlancoP,PaluckaAK,GillM,PascualV,BanchereauJ.Inductionofdendriticcelldiff
erentiationbyIFN-alphainsystemiclupuserythematosus.Science(2001)29 4: 1540–
3. d oi:10.1126/science.1064890
62. TrotteinF,PavelkaN ,VizzardelliC,AngeliV,ZouainCS,PelizzolaM,et al.
AtypeIIFN-dependentpathwayinducedbySchistosomamansonieggsinmousemyeloidde ndriticcellsgeneratesaninflammatorysignature.JImmunol(2004)1 7 2 : 3 0 1 1 – 7 . d oi:10.4049/jimmunol.172.5.3011
63. YoonJ,Leyva-CastilloJ M, WangG , Ga landC , OyoshiM K, KumarL , e t a l.
IL-23inducedinkeratinocytesbyendogenousTLR4ligandspolarizes
dendriticc ellstod r iveI L-22responsestoskini m munization.J ExpMed (2016)2 1 3 ( 1 0 ) : 2 1 4 7 –
6 6 . d oi:10.1084/jem.20150376
64. WillartMA,DeswarteK,PouliotP,BraunH,BeyaertR,LambrechtBN,etal.
Interleukin-1αc ontrolsa llergicsensitizationtoi n haledhousedustm itev iatheepithelialrelease ofGM- CSFandIL-33.J ExpMed(2012)209:1505–
17.doi:10.1084/jem.20112691
65. HammadH , C hieppaM , PerrosF,WillartM A , GermainR N , LambrechtBN.
Housedustm itea llergeni nducesasthmav iatoll-likereceptor4 t rig-geringofairwaystructuralc ells.NatMed( 2 0 0 9 ) 1 5 : 4 1 0 – 6 . d oi:10.1038/nm.1946
66. HammadH,PlantingaM,DeswarteK,PouliotP,WillartMAM,KoolM,etal.
Inflammatorydendriticcells–notbasophils–
arenecessaryandsufficientforinductionofT h 2 i m munitytoi n haledhousedustm it ea llergen.J ExpMed(2010)2 0 7 : 2 0 9 7 – 1 1 1 . d oi:10.1084/jem.20101563 67. MarichalT,BedoretD,MesnilC,PichavantM,GorielyS,TrotteinF,etal.
Interferonresponsef a ctor3 ise ssentialforhousedustm ite-inducedairwayallergy.JAllergyClinImmunol(2010)126(4):836.e–
44.e.doi:10.1016/j.jaci.2010.06.009
68. TaylorM J,C rossH F,BiloK . Inflammatoryresponsesi nducedbyt hef i larialnemat odeBrugiamalayiaremediatedbyl
ipopolysaccharide-likea ctivityfrome ndosymbioticWolbachiab acteria.J ExpMed(2 00 0) 1 91 :1 42 9 –3 6. doi:10.1084/jem.191.8.1429
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