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1、,1.引言 2.NLRP3炎性小体 3.NLRP3与IBD 4.总结,1.引言,IBD PAMPs/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 syn
2、drome，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
3、共同特征。 C-terminus 亮氨酸重复区(LRR),2.NLRP3 Inflamasome,distribution Structure Mechanisms of its activation Signal1:Priming Signal2:Activation Inhibition function,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
4、 NLRP1 can interact with 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 functi
5、onal N-terminal PYD, hence caspase-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 olig
6、omerization domain.,structure,激活剂,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
7、 NOD2, or cytokine receptors, such as TNFR and 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 domaincontainin
8、g Zn2+ metalloprotease deubiquitinating enzyme BRCC3,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 inflammas
9、ome activation. Type I IFNs acting through IFNAR inhibit 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 nitrosy
10、lation of NLRP3. Interaction of mature or memory T cells with 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 express
11、ion.,inhibition,Signal2:activation,Figure 4. Regulation of NLRP3 inflammasome 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
12、via receptors such as the purinergic receptor for ATP, P2X7R. During the 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
13、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
14、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（TNBS）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，
15、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, interleukin-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 im
16、munosorbent assay), synovial microvasculature cell adhesion (by intravital microscopy). Cleaved caspase 1 and 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
17、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,TeKippe 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):1045-1056 2.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,