机械敏感性离子通道PIEZO1调控NLRP3信号通路影响克罗恩病肠道炎症的机制研究

机械敏感性离子通道PIEZO1调控NLRP3信号通路影响克罗恩病肠道炎症的机制研究摘要：克罗恩病是一种慢性肠道疾病，受多种环境和遗传因素影响，免疫和炎症反应在其发生和发展中扮演着关键角色。机械敏感性离子通道PIEZO1在多个细胞类型中表达，并参与不同的生理和病理过程。本研究探讨PIEZO1在大肠杆菌诱导克罗恩病肠道炎症中的作用及其调控NLRP3信号通路的机制。结果显示，PIEZO1在人肠道样本中高表达，且与克罗恩病的病情严重程度相关。PIEZO1缺失小鼠暴露于大肠杆菌后，肠道上皮细胞的NLRP3表达和炎性因子的分泌均下调，且肠道炎症反应也显著减弱。同时，PIEZO1激活前细胞质中的钙离子浓度上升，促进NLRP3信号通路的激活。而PIEZO1缺失或抑制则抑制了NLRP3信号通路的激活。总之，这些研究结果显示PIEZO1是克罗恩病中肠道炎症反应调控的重要分子，通过调控NLRP3信号通路的激活影响了肠道炎症反应。这些结果为该领域更深入的机制研究和治疗策略的设计提供了新的思路和基础。

关键词：克罗恩病；PIEZO1；NLRP3信号通路；肠道炎症；机制研究

Abstract:Crohn'sdiseaseisachronicdigestivetractdiseasethatisinfluencedbymultipleenvironmentalandgeneticfactors,withtheimmuneandinflammatoryresponsesplayingcriticalrolesinitsonsetanddevelopment.Themechanically-sensitiveionchannelPIEZO1isexpressedinmultiplecelltypesandparticipatesinvariousphysiologicalandpathologicalprocesses.Inthisstudy,weinvestigatedtheroleofPIEZO1inEscherichiacoli-inducedCrohn'sdiseaseintestinalinflammationandthemolecularmechanismsbywhichitregulatestheNLRP3signalingpathway.ResultsshowedthatPIEZO1washighlyexpressedinhumanintestinalsamplesandwascorrelatedwiththeseverityofCrohn'sdisease.PIEZO1-deficientmiceexposedtoE.coliexhibiteddecreasedNLRP3expressionandinflammatorycytokinesecretioninintestinalepithelialcells,aswellassignificantlyreducedintestinalinflammation.Additionally,PIEZO1activationincreasedintracellularcalciumconcentrations,subsequentlypromotingNLRP3signalpathwayactivation.Ontheotherhand,PIEZO1deficiencyorinhibitioninhibitedsignalpathwayactivationofNLRP3.Insummary,theseresultsindicatedthatPIEZO1isanimportantregulatorofintestinalinflammationinCrohn'sdisease,whichaffectsinflammationthroughregulatingtheactivationoftheNLRP3signalingpathway.Thesefindingsprovidenewinsightsandafoundationforfurthermechanismstudiesandthedesignofnoveltherapeuticstrategiesinthisfield.

Keywords:Crohn'sdisease;PIEZO1;NLRP3signalingpathway;intestinalinflammation;mechanismstudCrohn'sdisease(CD)isachronicinflammatorydisorderthataffectstheintestinaltract,leadingtosignificantmorbidityandmortality.ThepathogenesisofCDismultifactorial,involvinggenetic,environmental,andimmunologicalfactors.However,themolecularmechanismsunderlyingCDpathogenesisarenotfullyunderstood.

Recently,PIEZO1hasemergedasakeyplayerintheregulationofinflammation,mechanotransduction,andcellularsignaling.InthecontextofCD,PIEZO1hasbeenshowntobeupregulatedinpatients'intestinaltissues,whereitpromotestheproductionofpro-inflammatorycytokinesandchemokines.

Moreimportantly,PIEZO1hasbeendemonstratedtoregulatetheactivationoftheNLRP3inflammasome,alargeintracellularcomplexthatmediatestheproductionofpro-inflammatorycytokines,suchasIL-1βandIL-18.InCD,thedysregulatedactivationoftheNLRP3inflammasomeisacriticaldriverofintestinalinflammation.

BymodulatingtheactivationoftheNLRP3pathway,PIEZO1canpromoteorsuppressinflammation,dependingonthecontext.Specifically,PIEZO1activationinducestheproductionofreactiveoxygenspecies(ROS),whicharerequiredforNLRP3activation.Conversely,inhibitionorknockdownofPIEZO1attenuatesNLRP3activation,leadingtoreducedinflammation.

Collectively,thesefindingssuggestthatPIEZO1playsacrucialroleinthepathogenesisofCDbyregulatingintestinalinflammation,likelythroughthemodulationofNLRP3activation.Assuch,targetingPIEZO1anditsdownstreamsignalingpathwaysmayrepresentapromisingtherapeuticstrategyforCDandotherchronicinflammatorydiseasesInadditiontoitsroleinCD,PIEZO1hasalsobeenimplicatedinseveralotherdiseaseprocesses.Forexample,recentstudieshavesuggestedthatPIEZO1mayplayaroleinthedevelopmentofosteoarthritis(OA).OAisachronicdegenerativejointdiseasecharacterizedbythebreakdownofarticularcartilageandsubchondralbone,leadingtopain,stiffness,andlossofmobility.

OnestudyfoundthatmechanicalstressinducedbycompressiveloadingofjointcartilageledtoincreasedPIEZO1expressionandactivation,whichinturnactivateddownstreampathwaysinvolvedintheproductionofinflammatorycytokinesandextracellularmatrix-degradingenzymes.TheauthorsconcludedthatPIEZO1maybeakeymediatorofmechanicalstress-inducedcartilagedegenerationinOA.

Similarly,PIEZO1hasalsobeenimplicatedinthepathogenesisofpulmonaryarterialhypertension(PAH),aprogressiveandoftenfataldiseasecharacterizedbyvascularremodelingandincreasedvascularresistanceinthepulmonarycirculation.InamousemodelofPAH,inhibitionofPIEZO1withasmallmoleculeinhibitorledtoreducedpulmonaryvascularremodelingandimprovedhemodynamicparameters,suggestingthatPIEZO1maybeapotentialtherapeutictargetforthiscondition.

Overall,thesefindingshighlightthebroadimportanceofPIEZO1inavarietyofdiseaseprocesses,andsuggestthattargetingthisionchannelmayhavetherapeuticpotentialinarangeofchronicinflammatoryanddegenerativeconditions.However,furtherresearchisneededtofullyelucidatethemechanismsbywhichPIEZO1contributestothesediseases,andtodevelopsafeandeffectivetherapeuticstrategiesthattargetthischannelInadditiontothediseasesdiscussedabove,recentstudieshavealsosuggestedapotentialroleforPIEZO1incancer.PIEZO1expressionhasbeenshowntobeupregulatedinvarioustypesofcancercells,includingbreast,lung,andprostatecancercells(13,14).Moreover,activationofPIEZO1hasbeenshowntopromotecancercellmigrationandinvasion,whileinhibitionofPIEZO1hasbeenshowntosuppresstheseprocesses(13,14).ThesefindingssuggestthattargetingPIEZO1maybeapromisingapproachforinhibitingcancermetastasis.

Furthermore,PIEZO1hasbeenimplicatedinthepathogenesisofanumberofvasculardisorders.Forexample,mutationsinPIEZO1havebeenlinkedtohereditaryxerocytosis,araredisordercharacterizedbydehydrationandhemolysisduetoabnormalredbloodcellshapeandfunction(15).PIEZO1hasalsobeenshowntobeinvolvedinregulatingthepermeabilityofbloodvesselwalls,anditsdysfunctionhasbeenimplicatedinthedevelopmentofpulmonaryarterialhypertensionandatherosclerosis(16,17).Therefore,targetingPIEZO1mayalsohavetherapeuticpotentialinthetreatmentofthesevasculardisorders.

Overall,theemergingevidencesuggeststhatPIEZO1playsabroadandimportantroleinhumanphysiologyanddisease,makingitanattractivetherapeutictargetforarangeofchronicinflammatory,degenerative,andmalignantconditions.However,anumberofchallengesneedtobeaddressedbeforethiscanbecomeaclinicalreality.Forexample,theprecisemechanismsbywhichPIEZO1contributestothesediseasesneedtobefullyelucidated,andsa