OverexpressionofVitaminDReceptorinIntestinalEpitheliaProtectsAgainstColitisviaUpregulatingTightJunctionProteinClaudin15.
肠上皮维生素D受体过度表达可通过上调紧密连接蛋白Claudin15来预防结肠炎。
Abstract
DysfunctionofthevitaminDreceptor(VDR)contributestotheetiologyofIBDbyregulatingautophagy,immuneresponse,andmucosalpermeability.VDRdirectlycontrolstheparacellulartightjunctionproteinClaudin-2.Claudin-2andClaudin-15areuniqueinmaintainingpara-cellularpermeability.Interestingly,claudin-15mRNAwasdownregulatedinpatientswithulcerativecolitis.However,theexactmechanismofClaudin-15regulationincolitisisstillunknown.Here,weinvestigatedtheprotectiveroleofVDRagainstintestinalinflammationviaupregulatingClaudin-15.WeanalyzedthecorrelationofClaudin-15withthereductionofVDRinhumancolitis.WegeneratedintestinalepithelialoverexpressionofVDR(O-VDR)micetostudythegain-of-functionofVDRincolitis.
功能紊乱的维生素D受体（VDR）通过调节自噬、免疫反应和黏膜通透性而引发了IBD。VDR直接控制细胞旁紧密连接蛋白Claudin-2。Claudin-2和Claudin-15在维持细胞旁通透性上起特殊作用。有趣的是，人们发现UC患者中Claudin-15mRNA表达下调。但人们目前对结肠炎中Claudin-15调控的确切机制尚未可知。在这里，我们研究了VDR通过上调Claudin-15起到对抗肠道炎症的保护作用。我们分析了Claudin-15与人类结肠炎中VDR降低的相关性。研究通过VDR（O-VDR）小鼠肠道上皮过表达，来研究VDR在结肠炎中的作用。
IntestinalepithelialVDRknockout(VDR?IEC)micewereusedfortheloss-of-functionstudy.ColonoidsandSKCO15cellswereusedasinvitromodels.ReducedClaudin-15wassignificantlycorrelatedwithdecreasedVDRalongthecolonicepitheliumofhumanIBD.O-VDRmiceshoweddecreasedsusceptibilitytochemical-andbacterial-inducedcolitisandmarkedincreasedClaudin-15expression(bothmRNAandprotein)inthecolon.Correspondingly,colonicClaudin-15wasreducedinVDR?IECmice,whichweresusceptibletocolitis.OverexpressionofintestinalepithelialVDRandvitaminDtreatmentresultedinasignificantlyincreasedClaudin-15.ChIPassaysidentifiedthedirectbindingofVDRtotheclaudin-15promoter,suggestingthatclaudin-15isatargetgeneofVDR.WedemonstratedthemechanismofVDRupregulationofClaudin-15toprotectagainstcolitis.ThismightenlightenthemechanismofbarrierdysfunctioninIBDandpotentialtherapeuticstrategiestoinhibitinflammation.
研究通过肠道上皮VDR基因敲除（VDR?IEC）小鼠来研究受体功能障碍；结肠和SKCO15细胞作为体外模型研究。我们在人IBD结肠上皮中观察到Claudin-15水平降低与VDR减少显著相关。O-VDR小鼠对化学和细菌性结肠炎的敏感性降低，并且结肠中Claudin-15表达（mRNA和蛋白）均明显升高。相应地，结肠Claudin-15在易感结肠炎的VDR?IEC小鼠中减少。肠上皮VDR的过表和维生素D治疗导致Claudin-15显著增加。ChIP分析明确了VDR与Claudin-15启动子的直接结合，表明Claudin-15是VDR的靶基因。研究证明了Claudin-15的VDR上调机制可预防结肠炎，其可能对明确IBD屏障功能障碍的机制以及对发现抑制炎症的潜在治疗策略有帮助。
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