Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity

Cryopyrin/NLRP3 信号在炎症和先天免疫中的作用

基本信息

批准号：
8764683
负责人：
Gabriel Nunez
金额：
$ 36.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764683
关键词：
Agonist Autoimmune Process Bacterial Toxins Biochemical Biochemical Genetics Biological Models Caspase Caspase-1 Cations Cells Crohn&apos s disease Cytosol Development Diabetes Mellitus Disease Enzyme Precursors Etiology Familial amyloid nephropathy with urticaria and deafness Familial disease Family Family member Genetic study Germ-Line Mutation Goals Gout Health Hemolysin Host Defense Human Immunity Infection Infectious Agent Inflammation Inflammatory Inherited Interleukin-18 Intracellular Membranes Invaded Laboratories Lead Ligands Link Lipoproteins Mediating Medical Missense Mutation Mitochondria Molecular Mutation NF-kappa B Natural Immunity Neonatal Particulate Matter Pathogenesis Pathway interactions Peptide Hydrolases Phagocytes Play Production Proteins Recruitment Activity Recurrence Regulation Role Sepsis Signal Pathway Signal Transduction Silicon Dioxide Skin Staphylococcus aureus Stimulus Streptococcus pyogenes Swelling Syndrome System TLR2 gene TNF gene Taurine Testing Toll-like receptors Toxin Urate Work antimicrobial bacterial hemolysin cytokine in vivo member microbial pathogen pathogenic bacteria procaspase-1 protein complex prototype receptor response secretion process

项目摘要

DESCRIPTION (provided by applicant): Caspase-1, a cysteine protease, is critical for the production of mature IL-1b and IL-18, two pro-inflammatory cytokines that play an important role in host defense, sepsis, and the pathogenesis of several inflammatory diseases. In addition, dysregulated IL-1b production is a causative factor in the development of autoinflammatory disorders including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multiple-system inflammatory disease. These inherited autoinflammatory syndromes are caused by missense mutations in NLRP3, a member of the NOD-like receptor (NLR) family. NLR family members including NOD1, NOD2, NLRC4 and NLRP3 are intracellular proteins that are involved in the recognition of microbial components and activation of inflammatory pathways against invading pathogens. Recent work from several laboratories including our own indicate that NLRP3 is critical for the activation of caspase-1 through its interaction with the adaptor molecule ASC and the formation of the inflammasome, a molecular platform that drives caspase-1 activation. We have obtained evidence that NLRP3 plays an important role in the activation of caspase-1 and IL-1b secretion in response to Toll-like receptor (TLR) ligands as well as infection with Staphylococcus aureus and Streptococcus pyogenes, two significant human pathogens. In addition, NLRP3 is critical for the activation of caspase-1 in response to particulate matter including silica and urate crystals. However, the molecular mechanism by which microbial and endogenous stimuli trigger caspase-1 activation via NLRP3 remains poorly understood. Our preliminary results revealed that TLR ligands and certain cytokines including TNF-a, IL-1a and IL-1b promote NLRP3-dependent caspase- 1 activation, at least in part, by the induction of NLRP3 via NF-kB. Unlike TLR agonists, we found that S. aureus and S. pyogenes activate the NLRP3 inflammasome via pore-forming toxins but independently of MyD88/TRIF and the purinergic P2X7 receptor. The goal of this proposal is to provide a better understanding of the mechanisms governing the activation and function of the NLRP3 inflammasome in response to ATP and bacterial toxins with a focus on ATP and S. aureus as model systems. Biochemical, genetic, and cellular approaches will be employed to study the function and activation of NLRP3. Given the important role of IL-1b in immunity and inflammatory disease, understanding of the mechanism involved in caspase-1 activation and IL-1b production via NLRP3 is expected to have a significant impact in the medical field

描述（由申请人提供）：Caspase-1 是一种半胱氨酸蛋白酶，对于成熟 IL-1b 和 IL-18 的产生至关重要，这两种促炎细胞因子在宿主防御、败血症和脓毒症的发病机制中发挥着重要作用。几种炎症性疾病。此外，IL-1b 产生失调是自身炎症性疾病（包括家族性感冒自身炎症综合征、Muckle-Wells 综合征和新生儿发病的多系统炎症性疾病）发展的致病因素。这些遗传性自身炎症综合征是由 NLRP3 错义突变引起的，NLRP3 是 NOD 样受体 (NLR) 家族的成员。 NLR 家族成员包括 NOD1、NOD2、NLRC4 和 NLRP3，它们是细胞内蛋白，参与微生物成分的识别和针对入侵病原体的炎症途径的激活。包括我们自己在内的多个实验室最近的工作表明，NLRP3 通过与接头分子 ASC 相互作用以及炎症小体（驱动 caspase-1 激活的分子平台）的形成，对于 caspase-1 的激活至关重要。我们已经获得证据表明，NLRP3 在响应 Toll 样受体 (TLR) 配体而激活 caspase-1 和 IL-1b 分泌以及金黄色葡萄球菌和化脓性链球菌（两种重要的人类病原体）感染中发挥重要作用。此外，NLRP3 对于激活 caspase-1 响应二氧化硅和尿酸盐晶体等颗粒物至关重要。然而，微生物和内源性刺激通过 NLRP3 触发 caspase-1 激活的分子机制仍知之甚少。我们的初步结果表明，TLR 配体和某些细胞因子（包括 TNF-a、IL-1a 和 IL-1b）至少部分通过 NF-kB 诱导 NLRP3 促进 NLRP3 依赖性 caspase-1 激活。与 TLR 激动剂不同，我们发现金黄色葡萄球菌和化脓性链球菌通过成孔毒素激活 NLRP3 炎症小体，但独立于 MyD88/TRIF 和嘌呤能 P2X7 受体。该提案的目的是更好地理解 NLRP3 炎症小体响应 ATP 和细菌毒素的激活和功能的机制，重点关注 ATP 和金黄色葡萄球菌作为模型系统。将采用生化、遗传和细胞方法来研究 NLRP3 的功能和激活。鉴于 IL-1b 在免疫和炎症性疾病中的重要作用，了解 caspase-1 激活和通过 NLRP3 产生 IL-1b 的机制预计将对医学领域产生重大影响

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Critical role for mast cells in interleukin-1β-driven skin inflammation associated with an activating mutation in the nlrp3 protein.

DOI：
10.1016/j.immuni.2012.04.013
发表时间：
2012-07-27
期刊：
Immunity
影响因子：
32.4
作者：
Nakamura Y;Franchi L;Kambe N;Meng G;Strober W;Núñez G
通讯作者：
Núñez G

Bacterial RNA mediates activation of caspase-1 and IL-1β release independently of TLRs 3, 7, 9 and TRIF but is dependent on UNC93B.

DOI：
10.4049/jimmunol.1103258
发表时间：
2012-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Eigenbrod T;Franchi L;Muñoz-Planillo R;Kirschning CJ;Freudenberg MA;Núñez G;Dalpke A
通讯作者：
Dalpke A

Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcδ.

DOI：
10.1371/journal.ppat.1003926
发表时间：
2014-02
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Suzuki S;Franchi L;He Y;Muñoz-Planillo R;Mimuro H;Suzuki T;Sasakawa C;Núñez G
通讯作者：
Núñez G

Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes.