Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation
2015
The cysteine protease caspase-1 (Casp-1) contributes to innate immunity through the assembly of NLRP3, NLRC4, AIM2, and NLRP6 inflammasomes. Here we ask whether caspase-1 activation plays a regulatory role in house dust mite (HDM)-induced experimental allergicairwayinflammation.Wereportenhancedairwayinflammationincaspase-1-deficientmiceexposedtoHDMwithamarkedeosinophilrecruitment,increasedexpressionofIL-4,IL-5,IL-13,aswellasfull-lengthandbioactiveIL-33.Furthermore,micedeficientfor NLRP3failedtocontroleosinophilinfluxintheairwaysanddisplayedaugmentedTh2cytokineandchemokinelevels,suggestingthat theNLPR3inflammasomecomplexcontrolsHDM-inducedinflammation.IL-33neutralizationbyadministrationofsolubleST2receptor inhibited the enhanced allergic inflammation, while administration of recombinant IL-33 during challenge phase enhanced allergic inflammationincaspase-1-deficient mice. Therefore,weshow thatcaspase-1,NLRP3,and ASC, but not NLRC4,contribute to the upregulationofallergiclunginflammation.Moreover,wecannotexcludeaneffectofcaspase-11,becausecaspase-1-deficientmicearedeficientforbothcaspases.Mechanistically,absenceofcaspase-1isassociatedwithincreasedexpressionofIL-33,uricacid,andspleen tyrosinekinase(Syk)production.Thisstudyhighlightsacriticalroleofcaspase-1activationandNLPR3/ASCinflammasomecomplexin the down-modulation of IL-33 in vivo and in vitro, thereby regulating Th2 response in HDM-induced allergic lung inflammation.
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