Regulation of cytosolic pattern recognition receptor signaling in macrophages

巨噬细胞胞质模式识别受体信号传导的调节

• 批准号: 8634013
• 负责人: Christian Stehlik
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-11 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634013
• 关键词: AIM2 gene; Acute; Adaptor Signaling Protein; Affect; Back; Bacterial Infections; Binding; Biological; Bone Marrow; Caspase; Caspase-1; Chronic; Communicable Diseases; Complex; Cytosol; Defect; Development; Disease; Equilibrium; Failure; Familial Mediterranean Fever; Family; Family member; Feedback; Francisella tularensis; Gene Transfer; Goals; Health; Homeostasis; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inherited; Interleukin-1; Interleukin-18; Invaded; Leucine-Rich Repeat; Link; Mediating; Modeling; Molecular; Mus; Mutation; Natural Immunity; Nomenclature; Nucleotides; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Positioning Attribute; Process; Production; Protein Family; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Simulate; Small Interfering RNA; Sterility; Symptoms; Testing; Time; Tissues; Transgenic Mice; Vaccinia virus; Viral; Virus Diseases; Work; base; combat; cytokine; design; feeding; human CASP4 protein; improved; in vivo; inflammatory modulation; macrophage; marenostrin; member; mouse model; mutant; novel; novel therapeutics; pathogen; prevent; procaspase-1; public health relevance; receptor; research study; response; secretion process; tool; treatment strategy

DESCRIPTION (provided by applicant): Invading pathogens are recognized by pattern recognition receptors (PRRs) of the innate immune system as a first line of defense. Activation of PRRs from the Nucleotide-binding and leucine-rich repeat containing (NLR) protein family and Absent in melanoma 2 (AIM2) in macrophages results in inflammasome formation. Inflammasomes are protein platforms that are essential for the activation of inflammatory Caspases and subsequently for the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1? and IL-18. Assembly of inflammasomes depends on PYRIN domain (PYD)-mediated recruitment of the adaptor protein ASC to activated PRRs, which then recruits pro-Caspase-1. In addition, Caspase-4, -5 and -8 participate. However, the molecular mechanism of inflammasome activation by cytosolic PRRs and in particular, regulation and termination of this process is poorly understood. We discovered a family of small proteins composed of only a PYD, called PYD-containing (PYDC or POP) proteins. We show that PYDCs function to inhibit inflammasome activation by blocking the PYD-PYD interactions essential for inflammasome formation. However, their precise role and contribution to in vivo host defense and inflammatory disease is still unknown. Inflammasomes are essential for host defense; however, inappropriate inflammasome activation also causes excessive and chronic inflammation, tissue destruction and the debilitating symptoms of the growing autoinflammatory diseases. Therefore, a balanced inflammasome response to allow pathogen clearance during acute infection, while preventing systemic inflammation through timely termination, is essential for homeostasis. We hypothesize that it is the role of the PYDC proteins to maintain this balanced inflammasome response through a negative feedback mechanism. Since PYDC proteins are lacking from mice, we generated novel mouse models to simulate the more complex inflammasome regulation evolved in humans. We propose to determine PYDC-mediated inflammasome regulation and termination during all known scenarios of inflammasome activation: pathogen infection/pathogen-associated molecular pattern (PAMP), tissue damage/damage associated molecular pattern (DAMP) and hereditary PRR mutation in macrophages and in vivo. We will focus on select inflammasome-activating PRRs. In aim 1 we will determine the molecular mechanism of inflammasome regulation and termination for each PYDC ex vivo in macrophages and in aim 2 we propose to determine PYDC-mediated inflammasome regulation in vivo. Collectively, our study is designed to establish the specific inflammasome regulatory function of the PYDC family during infection and inflammatory disease, which we expect will significantly advance our understanding of fundamental biological principles underlying innate immunity, host defense and inflammatory disease and the mechanism by which these responses are regulated.

描述（由申请人提供）：入侵病原体是由先天免疫系统的模式识别受体（PRR）确认为第一道防线。巨噬细胞中黑色素瘤2（AIM2）中含有核苷酸结合和富含亮氨酸重复蛋白的核苷酸结合和富含亮氨酸重复的PRR激活导致炎症体的形成。炎性症是蛋白质平台，对于炎症性胱天蛋白酶的激活以及随后的促炎性细胞因子白介素（IL）-1的成熟和释放至关重要？和IL-18。炎性症的组装取决于吡啶结构域（PYD）介导的衔接蛋白ASC募集到激活的PRR，然后募集Pro-Caspase-1。此外，Caspase -4，-5和-8也参加。然而，对胞质PRR的炎性体激活的分子机制，尤其是该过程的调节和终止。我们发现了一个仅由PYD组成的小蛋白质，称为含PYD（PYDC或POP）蛋白质。我们表明，PYDC通过阻断炎症体形成必不可少的PYD-PYD相互作用来抑制炎症体激活。但是，它们对体内宿主防御和炎症性疾病的确切作用和贡献仍然未知。炎症对于宿主防御至关重要。然而，不适当的炎性体激活还会导致过度和慢性炎症，组织破坏以及日益增长的自发性疾病的衰弱症状。因此，对急性感染期间病原体清除的平衡炎症反应，同时防止全身性炎症通过及时终止，对于稳态至关重要。我们假设，通过负反馈机制维持这种平衡的炎性体反应是PYDC蛋白的作用。由于小鼠缺乏PYDC蛋白，因此我们生成了新型的小鼠模型，以模拟人类进化的更复杂的炎性体调节。我们建议在所有已知的炎症体激活中确定PYDC介导的炎性体调节和终止：病原体感染/病原体相关的分子模式（PAMP），组织损伤/损伤相关的分子模式（DAMP）和遗传性PRR突变，巨噬细胞和体内。我们将专注于精选的炎性激活PRR。在AIM 1中，我们将确定巨噬细胞中每个PYDC的炎性体调控和终止的分子机制，在AIM 2中，我们建议确定PYDC介导的体内炎性体调节。总的来说，我们的研究旨在在感染和炎症性疾病期间建立PYDC家族的特定炎症体调节功能，我们期望这将大大提高我们对先天免疫，宿主防御和炎症性疾病以及这些反应的机制的基本生物学原理的理解。