TREM-1 in Lung Immune Response

TREM-1 在肺部免疫反应中的作用

• 批准号: 8803331
• 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/8803331
• 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; Health; 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; Pulmonary Inflammation; 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; 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的主要死亡原因。铜绿假单胞菌肺炎的抗生素治疗失败率很高，在治疗过程中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，如核苷酸寡聚区，与TLRs合作，并在定义先天宿主对细菌的反应中至关重要。髓样细胞上表达的触发受体1(TREM-1)是巨噬细胞和中性粒细胞上表达的超级免疫球蛋白家族的成员。阻断TREM-1可提高脓毒症致死性动物模型的存活率。因此，这些受体正在成为TLR启动的炎症反应的强大放大器，然而，关于细菌对TREM-1表达的调节机制的数据有限，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。我们是第一个证明内毒素激活TREM-1受转录控制的人(1)。当核因子-βB激活TREM-1基因时，PU.1抑制内毒素对TREM-1的表达。其次，我们已经证明了MyD88依赖和独立的信号决定了特定TLR配体反应中TREM-1的表达(2)。我们还定义了在巨噬细胞中沉默TREM-1基因的功能后果，其中包括改变TLR4激活下游的关键信号分子的可用性(3)。我们的新数据显示，在对铜绿假单胞菌和败血症肺损伤的人肺中，TREM-1在小鼠体内被诱导。巨噬细胞中TREM-1的激活通过上调IL-6和IL-23等关键生物分子，为TLR诱导的炎症提供正反馈，从而夸大炎症，阻碍巨噬细胞体外杀菌的免疫能力。总而言之，这些数据表明TLR和TREM-1信号之间存在显著的串扰，并表明TREM-1在定义宿主免疫反应中起着关键作用。最重要的是，通过使用新的纳米胶束制剂，我们已经在体内证明了阻断TREM-1可以减轻小鼠的肺部炎症。总体而言，我们发表的和初步的研究表明，在这一应用中需要寻求两种全新的机制：(1)通过转录调控和对细菌的表观遗传修饰来表达TREM-1；(2)通过遗传和新颖的纳米药物方法，通过TREM-1信号夸大炎症和抑制宿主对入侵细菌的保护反应的机制。我们的发现导致了这样的假设，即铜绿假单胞菌对TREM-1的激活受NF-βB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特定目标：1)明确p65和PU.1在体外调节巨噬细胞对铜绿假单胞菌反应的TREM-1表达的分子机制。2)阐明巨噬细胞和体内TREM-1信号在铜绿假单胞菌感染的宿主免疫应答中的作用。3)开发新型的TREM-1封闭纳米胶束，用于铜绿假单胞菌肺炎的免疫调节治疗。铜绿假单胞菌引起的医院内肺炎是危重病人发病率和死亡率的主要原因，退伍军人事务部是全球最大的危重护理服务提供者。这些研究的完成将提供对TREM-1在肺部免疫反应中的贡献的深入了解，并将为开发免疫调节疗法奠定基础，这种疗法将对铜绿假单胞菌等威胁生命的感染的治疗产生重大影响。