Regulation of Innate Immunity by Pyrin Proteins

描述（由申请人提供）：TLR和NLR家族成员的细胞外和细胞内病原体识别启动先天性免疫和炎症反应。TLR和NLR都激活NF-？B和MAPK信号通路导致多种炎性细胞因子（例如TNF 1、IL-6和IL-8）的转录和分泌。与TLR不同，NLR还可以激活多蛋白炎性体复合物，其将proIL-12和proIL-18加工成其活性形式。在不到五年的时间里，NLR已经与遗传性自身炎症性疾病和对越来越多的病原体的先天免疫反应有关，包括炭疽杆菌，鼠疫耶尔森菌和土拉弗朗西斯菌。炎性体组装是由含有pyrin的NLR蛋白与ASC（具有CARD的凋亡斑点蛋白）的相互作用，随后是半胱天冬酶-1的募集和活化引起的。炎性体复合物也可能参与诱导一种形式的半胱天冬酶-1依赖性细胞凋亡。ASC与NLR和Pyrin蛋白的相互作用也可以激活NF-？B。最近，发现的pyrin只有蛋白质（持久性有机污染物），影响NF-？B和炎性体功能已经提示了宿主调节促炎反应及其病原体颠覆的途径。这项建议的长期目标是了解依赖于pyrin only蛋白质的先天免疫反应的分子调控。此外，对炎性小体调节的理解将扩展到宿主-病原体相互作用，其中炎性小体功能或颠覆被证明对免疫或疾病至关重要。具体而言，我们已经确定了第二个人POP（POP 2），抑制NF-？B p65活性，与ASC相互作用，并阻止许多NLR激活的炎性小体的激活。我们将测试的假设，POP 2负调节炎症反应的干扰炎症体介导的caspase-1激活和衰减NF-？B信号，从而抑制有害的炎症并防止或减少先天免疫应答期间的巨噬细胞死亡。结合广泛基础的分子和体内方法，我们将解决以下目标：1）建立NF-？2）建立POP 2调节炎性小体活化的分子基础。3)建立POP 2在调节炎性先天免疫应答中的体内作用。公共卫生相关性：损伤或感染引起的炎症反应是对人类健康的重大威胁。我们建议研究一种名为POP 2的小蛋白，它在炎症细胞中表达，可以调节导致炎症的细胞事件。因此，这项研究与从感染到心血管疾病的各种炎症性疾病和病症有关。

DESCRIPTION (provided by applicant): Extracellular and intracellular pathogen recognition by members of the TLR and NLR families initiate innate immune and inflammatory responses. TLRs and NLRs both activate the NF-?B and MAPK signaling pathways leading to the transcription and secretion of multiple inflammatory cytokines (e.g. TNF1, IL-6, and IL-8). Unlike TLRs, NLRs can also activate multiprotein inflammasome complexes that processes proIL-12 and proIL-18 to their active forms. In less than five years, NLRs have been linked to hereditary autoinflammatory diseases and innate immune response towards a growing number of pathogens, including Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Inflammasome assembly results from interaction of a pyrin containing NLR protein with ASC (apoptotic speck protein with a CARD) followed by recruitment and activation of Caspase-1. The inflammasome complex may also be involved in inducing a form of caspase-1 dependent apoptosis. ASC interactions with NLRs and the protein Pyrin can also activate NF-?B. Recently, the discovery of pyrin only proteins (POPs) that influence both NF-?B and inflammasome functions has suggested an avenue for host regulation of the proinflammatory response and pathogen subversion thereof. The long-term objective of this proposal is to understand the molecular regulation of innate immune responses dependent upon pyrin only proteins. Further, understanding of inflammasome regulation will be extended to host-pathogen interactions where inflammasome function or subversion is demonstrated to be critical for immunity or disease. Specifically, we have identified a second human POP (POP2) which inhibits NF-?B p65 activity, interacts with ASC, and prevents the activation of a number of NLR activated inflammasomes. We will test the hypothesis that POP2 negatively regulates proinflammatory responses by interfering with both inflammasome-mediated caspase-1 activation and attenuating NF-?B signals, thus dampening harmful inflammation and preventing or reducing macrophage death during innate immune responses. Combining broad based molecular and in vivo approaches, we will address the following aims: 1) Establish the molecular basis for NF-?B inhibition by POP2 2) Establish the molecular basis for POP2 regulation of inflammasome activation. 3) Establish the in vivo role of POP2 in modulating inflammatory innate immune responses. PUBLIC HEALTH RELEVANCE: Inflammatory responses resulting from injury or infection are a significant threat to human health. We propose to study a small protein called POP2 which is expressed in inflammatory cells and can regulate cellular events leading to inflammation. This study is therefore relevant to a wide range of inflammatory diseases and conditions, ranging from infection to cardiovascular disease.