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）： 翻译后摘要：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生有关。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如核苷酸寡聚化结构域与TLR合作，并且在定义对细菌的先天宿主应答中至关重要。 髓样细胞表达触发受体1（TREM-1）是在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可提高败血症致死动物模型的存活率。因此，这些受体作为TLR引发的炎症反应的有效放大剂出现，然而，关于TREM-1表达响应于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或没有。我们是第一个表明响应LPS的TREM-1激活是转录控制的（1）。当NF-B激活TREM-1基因时，PU. 1抑制TREM-1响应于LPS的表达。其次，我们已经表明，MyD 88依赖性和独立性信号传导决定了TREM-1响应于特异性TLR配体的表达（2）。我们还确定了沉默巨噬细胞中TREM-1基因的功能后果，包括TLR 4活化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在小鼠体内响应铜绿假单胞菌和感染性肺损伤的人肺中诱导。巨噬细胞中的TREM-1活化通过上调关键生物分子如IL-6和IL-23提供对TLR诱导的炎症的正反馈，从而夸大炎症并阻碍巨噬细胞在体外杀死细菌的免疫能力。这些数据一起表明TLR和TREM-1信号传导之间的显著串扰，并表明TREM-1在定义宿主免疫应答中的关键作用。最重要的是，通过使用新型纳米胶束制剂，我们已经表明TREM-1的阻断在体内减弱小鼠的肺部炎症。 作为一个整体，我们发表的和初步的研究表明，在本申请中要追求两个根本上新的机制：（1）TREM-1表达的转录控制和表观遗传修饰响应于细菌（2）TREM-1信号转导夸大炎症和抑制宿主的保护性反应入侵细菌使用遗传和新的纳米医学方法的机制。我们的研究结果导致了这样的假设，即响应于铜绿假单胞菌的TREM-1的激活受NF-B和PU的调节。巨噬细胞中的TREM-1活化在确定宿主对细菌的反应中起关键作用。因此，TREM-1的阻断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）定义TREM-1表达的分子机制是由p65和PU.1在体外巨噬细胞响应铜绿假单胞菌。2)阐明TREM-1信号传导在巨噬细胞中和体内在对铜绿假单胞菌感染的宿主免疫应答中的作用。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医院内肺炎是危重患者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重症监护服务提供者。这些研究的完成将提供对TREM-1在肺免疫应答中的贡献的深入理解，并将为开发免疫调节疗法奠定基础，这些疗法将对治疗危及生命的感染（如铜绿假单胞菌）产生重大影响。