Toll‐like receptor 4‐interacting SPA4 peptide suppresses the NLRP3 inflammasome in response to LPS and ATP stimuli

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: immunomodulation;    anti‐;    inflammatory activity;    surfactant protein A;   

DOI  :  10.1189/jlb.3A1114-570R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Inflammationisinducedbecauseofinterplayamongmultiplesignalingpathwaysandmoleculesduringinfectiousandnoninfectioustissueinjuries.CrosstalkbetweenToll‐likereceptor‐4signalingandtheneuronalapoptosisinhibitorprotein,majorhistocompatibilityclass2transcriptionactivator,incompatibilitylocusproteinfromPodosporaanserina,andtelomerase‐associatedprotein(NACHT),leucine‐richrepeat(LRR),andpyrindomain‐containingprotein3(NLRP3)inflammasomeagainstpathogen‐ordamage‐associatedmolecularpatternscancauseexaggeratedinflammation.WepreviouslyestablishedthattheToll‐likereceptor‐4‐interactingSPA4peptidesuppressesgram‐negativebacteriallipopolysaccharide(Toll‐likereceptor‐4ligand)‐inducednuclearfactor‐κBandinflammatoryresponse.Inthepresentstudy,wehypothesizedthattheSPA4peptideexertsitsanti‐inflammatoryeffectsbysuppressingthecrosstalkbetweenToll‐likereceptor‐4signalingandtheNLRP3inflammasome.Weevaluatedbindingofthelipopolysaccharide‐ligandtocell‐surfaceToll‐likereceptor‐4inthepresenceorabsenceofadenosinetriphosphate(anNLRP3inflammasomeinducer)byflowcytometry.TheexpressionandactivityofNLRP3inflammasome‐relatedparameterswerestudiedincellschallengedwithlipopolysaccharideandadenosinetriphosphateusingmolecularandimmunologicmethods.ThecellswerechallengedwithlipopolysaccharideandtreatedwithSPA4peptidebefore(pre‐adenosinetriphosphate)orafter(post‐adenosinetriphosphate)secondarychallengewithadenosinetriphosphate.OurdatademonstratethattheToll‐likereceptor‐4‐interactingSPA4peptidedoesnotaffectthebindingoflipopolysaccharidetoToll‐likereceptor‐4inthepresenceorabsenceofadenosinetriphosphate.WealsofoundthattheSPA4peptideinhibitsmRNAandcellularproteinlevelsofpro‐interleukin‐1βandNLRP3,formationoftheNLRP3inflammasome,caspaseactivity,andreleaseofinterleukin‐1β.Furthermore,theSPA4peptidetreatmentreducedthesecretedlevelsofinterleukin‐1βfromcellsoverexpressingToll‐likereceptor‐4comparedwithcellsexpressingthedominant‐negativeformofToll‐likereceptor‐4.TogetherourresultssuggestthattheSPA4peptideexertsitsanti‐inflammatoryactivitybysuppressingToll‐likereceptor‐4‐primingoftheNLRP3inflammasome..

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