TREM-1 in Lung Immune Response

TREM-1 在肺部免疫反应中的作用

• 批准号: 8667934
• 负责人: Ruxana T Sadikot
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667934
• 关键词: Adoptive Transfer; Amplifiers; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Attenuated; Bacteria; Binding; Cause of Death; Characteristics; Complex; Critical Care; Critical Illness; Data; Development; Drug Formulations; Drug Kinetics; Epigenetic Process; Failure; Family; Feedback; Functional disorder; Future; Gene Activation; Genes; Genetic; Goals; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immunoglobulins; In Vitro; Infection; Inflammation; Inflammatory Response; Intensive Care Units; Interleukin-6; Invaded; Knock-out; Knockout Mice; Life; Ligands; Lung; Lung Inflammation; Macrophage Activation; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Mutagenesis; Myeloid Cells; NF-kappa B; Nosocomial pneumonia; Nucleotides; Organ; Pathogenesis; Patients; Peptides; Phagocytosis; Pharmacodynamics; Play; Pneumonia; Preparation; Proteins; Provider; Pseudomonas aeruginosa; Publishing; Regulation; Role; SPI1 gene; Sepsis; Services; Signal Transduction; Signaling Molecule; Site; Syndrome; TLR4 gene; Transcriptional Regulation; Veterans; Work; abstracting; gain of function; immunoglobulin receptor; immunoregulation; improved; in vivo; interleukin-23; killings; lung injury; macrophage; member; mortality; nanocarrier; nanomedicine; neutrophil; novel; novel therapeutics; p65; pathogen; promoter; public health relevance; receptor; response; septic

DESCRIPTION (provided by applicant): Abstract: Lung infections and sepsis caused by P.aeruginosa are a leading cause of death in the intensive care unit. The failure rate for antibiotic treatment for P. aeruginosa pneumonia is high and antibiotic resistance that develops during therapy is associated with persistent pneumonia and development of multi-organ dysfunction syndrome. Therefore there is an urgent need to develop immunomodulatory strategies for P.aeruginosa lung infections. It is becoming evident that immunoglobulin receptors and intracellular proteins such as nucleotide oligomerization domains co-operate with TLRs and are critical in defining the innate host response to bacteria. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on macrophage and neutrophils. Blockade of TREM-1 improves survival in lethal animal models of sepsis. These receptors are thus emerging as potent amplifiers of TLR initiated inflammatory responses however there is limited data on the mechanisms by which TREM-1 expression is regulated in response to bacteria and there is little to no information about how these receptors modulate host response to invading pathogens. We were the first to show that TREM-1 activation in response to LPS is transcriptionally controlled (1). While NF-¿B activates the TREM-1 gene, PU.1 inhibits the expression of TREM-1 in response to LPS. Second, we have shown that MyD88 dependent and independent signaling determines the expression of TREM-1 in response to specific TLR ligands (2). We have also defined the functional consequences of silencing TREM-1 gene in macrophages which include altered availability of key signaling molecules downstream of TLR4 activation (3). Our new data shows that TREM-1 is induced in vivo in mice in response to P.aeruginosa and in human lungs with septic lung injury. TREM-1 activation in macrophages provides a positive feedback to the TLR induced inflammation by upregulating key biomolecules such as IL-6 and IL-23 thus exaggerating inflammation and impeding the immune capacity of macrophages to kill bacteria in vitro. Together these data indicate a significant crosstalk between TLR and TREM-1 signaling and suggest a key role for TREM-1 in defining the host immune response. Most importantly by using novel nanomicellar preparation we have shown that blockade of TREM-1 attenuates lung inflammation in mice in vivo. As a whole our published and preliminary studies suggest two fundamentally new mechanisms to be pursued in this application: (1) TREM-1 expression by transcriptional control and epigenetic modification in response to bacteria (2) mechanisms by which TREM-1 signaling exaggerates inflammation and inhibits host protective response to invading bacteria using genetic and novel nanomedicine approach. Our findings have led to the hypothesis that activation of TREM-1 in response to P.aeruginosa is regulated by NF-¿B and PU.1. TREM-1 activation in macrophages plays a pivotal role in defining the host response to bacteria. Thus blockade of TREM-1 will enhance host immune capacity to P.aeruginosa lung infections. We propose three interrelated specific aims:1) Define the molecular mechanisms by which TREM-1 expression is regulated by p65 and PU.1 in vitro in macrophages in response to P.aeruginosa. 2) Elucidate the role of TREM-1 signaling in macrophages and in vivo in host immune response to P. aeruginosa infection. 3) Develop novel TREM-1 blocking nanomicelles for immunomodulatory therapies for P.aeruginosa pneumonia. Nosocomial pneumonia caused by P.aeruginosa is a leading cause of morbidity and mortality in critically ill patients and the Department of Veterans Affairs is the largest worldwide single provider of critical care services. Completion of these studies will provide an in depth understanding of the contribution of TREM-1 in lung immune response and will lay the ground work for developing immunomodulatory therapies that will have a significant impact on treatment of life threatening infections such as P.aeruginosa.

描述（由申请人提供）： 摘要： 铜绿假单胞菌引起的肺部感染和败血症是重症监护病房死亡的主要原因。铜绿假单胞菌肺炎的抗生素治疗失败率很高，治疗期间产生的抗生素耐药性与持续性肺炎和多器官功能障碍综合征的发展有关。因此，迫切需要开发针对铜绿假单胞菌肺部感染的免疫调节策略。越来越明显的是，免疫球蛋白受体和细胞内蛋白质（例如核苷酸寡聚化结构域）与 TLR 协同作用，对于定义宿主对细菌的先天反应至关重要。 骨髓细胞表达的触发受体 1 (TREM-1) 是巨噬细胞和中性粒细胞表达的超级免疫球蛋白家族的成员。 TREM-1 的阻断可提高脓毒症致死动物模型的存活率。因此，这些受体成为 TLR 引发的炎症反应的有效放大器，然而，关于 TREM-1 表达响应细菌而调节的机制的数据有限，并且关于这些受体如何调节宿主对入侵病原体的反应的信息很少甚至没有。我们首次证明 LPS 响应的 TREM-1 激活是受转录控制的 (1)。 NF-¿B 激活 TREM-1 基因，而 PU.1 响应 LPS 抑制 TREM-1 的表达。其次，我们证明 MyD88 依赖性和独立信号传导决定了响应特定 TLR 配体的 TREM-1 表达 (2)。我们还定义了巨噬细胞中 TREM-1 基因沉默的功能后果，其中包括 TLR4 激活下游关键信号分子的可用性改变 (3)。我们的新数据表明，TREM-1 在小鼠体内被诱导，以响应铜绿假单胞菌，并且在患有脓毒性肺损伤的人肺部中被诱导。巨噬细胞中的 TREM-1 激活通过上调 IL-6 和 IL-23 等关键生物分子，为 TLR 诱导的炎症提供正反馈，从而加剧炎症并阻碍巨噬细胞在体外杀死细菌的免疫能力。这些数据共同表明 TLR 和 TREM-1 信号传导之间存在显着的串扰，并表明 TREM-1 在定义宿主免疫反应中发挥着关键作用。最重要的是，通过使用新型纳米胶束制剂，我们已经证明 TREM-1 的阻断可减轻小鼠体内的肺部炎症。 总的来说，我们已发表的初步研究表明该应用中需要追求两种全新的机制：（1）通过转录控制和表观遗传修饰来表达TREM-1以响应细菌（2）TREM-1信号传导夸大炎症并使用遗传和新型纳米医学方法抑制宿主对入侵细菌的保护性反应的机制。我们的研究结果得出这样的假设：TREM-1 响应铜绿假单胞菌的激活受到 NF-¿B 和 PU.1 的调节。巨噬细胞中 TREM-1 的激活在确定宿主对细菌的反应中起着关键作用。因此，阻断TREM-1将增强宿主对铜绿假单胞菌肺部感染的免疫能力。我们提出了三个相互关联的具体目标：1) 明确巨噬细胞中 p65 和 PU.1 体外调节 TREM-1 表达以响应铜绿假单胞菌的分子机制。 2) 阐明 TREM-1 信号在巨噬细胞和体内宿主对铜绿假单胞菌感染的免疫反应中的作用。 3) 开发新型 TREM-1 阻断纳米胶束，用于铜绿假单胞菌肺炎的免疫调节治疗。由铜绿假单胞菌引起的院内肺炎是危重患者发病和死亡的主要原因，退伍军人事务部是全球最大的重症监护服务单一提供者。这些研究的完成将深入了解 TREM-1 在肺部免疫反应中的贡献，并将为开发免疫调节疗法奠定基础，这将对治疗铜绿假单胞菌等危及生命的感染产生重大影响。