最新NLRP3炎性小体与炎症性肠病PPT文档.pptx

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1、,1.引言2.NLRP3炎性小体3.NLRP3与IBD 4.总结,1.引言,IBDPAMPs/DAMPs与PRRs(TLRs/NLRs)NF-B通路炎性小体(*NLRs/ASC/Caspase/AIM2),NLRP3 炎性小体的活化可致无活性的caspase-1 前体转化为活性caspase-1，后者可裂解白细胞介素（IL-1）、IL-18、IL-33 前体以形成活性形式并分泌。NLRP3 已证实与人类多种自身免疫病相关，如家族性寒冷自身炎症综合征（familial cold utoinflammatory syndrome,FCAS）、穆-韦综合征（Muckle-Wells syndrome

2、，MWS）和新生儿期多系统炎症综合征（neonatal onset ultisystem inflammatory disease,NOMID），上述疾病统称为隐热蛋白-相关周期综合征（cryopyrin associated periodic syndrome,CAPS）。,NLRs,N-terminal 效应区 含有一个热蛋白结构域(PYD),caspase招募结构域(CARD),或一个杆状病毒凋亡抑制重复结构域(BIR),NLRs亚类的分类依据（NLRA/NLRB/NLRC/NLRP/NLRX）。Central 核苷酸结合寡聚化结构域(NACHT），是各种NLRs的共同特征。C-term

3、inus 亮氨酸重复区(LRR),2.NLRP3 Inflamasome,distributionStructureMechanisms of its activationSignal1:PrimingSignal2:ActivationInhibitionfunction,分布,NLRP3 在中性粒细胞、单核细胞、淋巴细胞、树突细胞、成骨细胞、上皮细胞（口咽部、食管、外宫颈、尿道）、皮肤角质形成细胞等均有表达。,Figure 1.Schematic of NLRP1,NLRP3,NLRC4,and AIM2 inflammasomes.Human NLRP1 can interact wit

4、h ASC and caspase-1 via an N-terminal PYD and also bind caspase-5 to the complex via the C-terminal CARD.Muramyl dipeptide(MDP),Bacillus anthracis lethal toxin,and Toxoplasma gondii can induce the activation of the NLRP1 inflammasome.Mouse Nlrp1b does not possess a functional N-terminal PYD,hence ca

5、spase-1 may interact with its C-terminal CARD.NLRP3 interacts with ASC through an N-terminal PYD domain,which then recruits caspase-1.Mitochondrial DNA(mtDNA)and cardiolipin have been postulated to bind to NLRP3 and induce its activation.,nucleotide-binding and oligomerization domain.,structure,激活剂,

6、NLRP3炎症小体是目前研究最为深人的一种炎症小体,可被多种病原体及其成分或产物激活,如金黄色葡萄球菌、李斯特菌、白色念珠菌、酿酒酵母菌、仙台病毒、细菌RNA、尼利亚菌素等;内源性损伤信号或环境致病因子,如胞外ATP、尿酸钠晶体、二氧化硅、紫外线等亦可激活NLRP3炎症小体。,Figure2.Signals mediating NLRP3 inflammasome priming.Upon engagement,patternrecognition receptors(PRR),such as TLR4 and NOD2,or cytokine receptors,such as TNFR a

7、nd IL-1R,activate NF-B,leading to the transcription and translation of NLRP3 and pro-IL-1.Dissociation of HSP90 and SGT1 from NLRP3 is required for NLRP3 inflammasome activation.Additionally,NLRP3 undergoes deubiquitylation by the JAMM domaincontaining Zn2+metalloprotease deubiquitinating enzyme BRC

8、C3,which is crucial for subsequent NLRP3 inflammasome activation.Upon activation of the NLRP3 inflammasome,active caspase-1 can process pro-IL-1 and pro-IL-18 into their mature secreted forms.,Signal1:priming,Figure 3.Inhibition of NLRP3 inflammasome activation.Type I IFNs acting through IFNAR inhib

9、it the transcription of pro-IL-1 through the upregulation of the anti-inflammatory cytokine IL-10.Type I IFNs and IFN-inhibit NLRP3 through the production of nitric oxide(NO)via the inducible nitric oxide synthase(iNOS),resulting in nitrosylation of NLRP3.Interaction of mature or memory T cells with

10、 macrophages via CD40CD40L results in inhibition of the NLRP3 inflammasome.Elevation of cellular cAMP levels also results in the inhibition of NLRP3.The microRNA miR-223 regulates the amount of NLRP3 mRNA and,consequently,NLRP3 expression.,inhibition,Signal2:activation,Figure 4.Regulation of NLRP3 i

11、nflammasome activation in response to ion fluxes and mitochondrial dysfunction.K+efflux is required for NLRP3 inflammasome activation and is achieved either directly by bacterial pore-forming toxins,such as nigericin,or indirectly via receptors such as the purinergic receptor for ATP,P2X7R.During th

12、e regulatory volume decrease response to cell swelling,Ca2+fluxes can be regulated by the transient receptor potential receptors TRPM7 and TRPV2.Ca2+influx can also be mediated via the ROS-sensitive TRPM2.,可能的激活机制,ATP-依赖的钾离子外流线粒体功能障碍ROS溶酶体破裂核糖体功能障碍,3.NLRP3炎性小体与IBD,(1)CD遗传易感性,2001 年，McGovern等发现了CD 的第

13、一个易感基因NOD2/CARD15，因NLRP3和NOD2 蛋白同属NLR 家族成员，由此提示NLRP3 亦可能与CD 相关。对瑞典人的研究发现NLRP3炎症小体组分N LRP3、CARDS8基因多态性与NOD2 等位基因为野生型的男性的CD 易感性相关;对加拿大欧洲后裔的研究发现位于NLRP3 基因下游调控区的一组SN Ps 与C D易感性相关,但该相关性未能在英联邦人群中被复制,表明此种相关性受地域和遗传背景的影响。,(2)IBD小鼠的相关研究,今年有研究发现NLRP3炎症小体组分缺陷(NLRP3-/-或ASC-/-或Caspase-1-/-)小鼠对葡聚糖硫酸钠(DSS)或三硝基苯磺酸（T

14、NBS）诱导的结肠炎更为易感。给予重组IL-18可使caspase-1缺陷小鼠的重量减轻明显缓解,表明NLRP3炎症小体通过IL-18 对实验性结肠炎发挥保护作用,发挥作用的主要是肠上皮细胞中的NLR P3 炎症小体。然而亦有研究发现NLRP3-/-小鼠对DS 诱导的结肠炎耐受,其机制可能与结肠促炎细胞因子IL-1、IL-18、肿瘤坏死因子-(TNF-)等产生减少有关。实验结果的不一致性可能是由实验小鼠的遗传背景，肠道菌群组成以及实验干预方案不同所引起。,(3)材料与方法,Wild-type mice and mice deficient in NLRP3,ASC,caspase 1,inte

15、rleukin-1(IL-1),IL-1 receptor type I(IL-1RI),IL-18R,myeloid differentiation factor 88(MyD88),or 5-LOX were used.neutrophil influx,LTB4 activity,cytokine(IL-1,CXCL1)production(by enzyme-linked immunosorbent assay),synovial microvasculature cell adhesion(by intravital microscopy).Cleaved caspase 1 and

16、 production of reactive oxygen species(ROS)were analyzed in macrophages by Western blotting and fluorometric assay,respectively.,4.总结,虽然对NLRP3炎性小体的研究非常广泛，但不够深入。炎性小体组装的激活信号通路还不清楚，如细胞钾离子外流如何激活炎性体，线粒体如何发挥作用。目前，NLRP3炎性体与肠道炎症的研究很少，炎性体信号通路参与包括IBD在内的一些炎症性疾病，可作为治疗IBD的药物靶点，对其研究有助于发现新型的治疗药物。,参考文献,1.Allen IC,T

17、eKippe M,Woodford RM,et al.The NLRP3 inflamasome funtions as a negative regulator of tumorigenesis during colitis-assocaited cancer J.J Exp Med,2010,207(5):1045-10562.Zaki MH,Boyd KL,Vogel P,et al.The NLRP3 inflamasome protects against loss of epithelial integrity and mortality during experimental colitis J.Immunity,2010,32(3):379-391,