Innate priming in sepsis exacerbation

脓毒症恶化中的先天启动

• 批准号: 8882579
• 负责人: LIWU LI
• 金额: $ 40.25万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-14 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882579
• 关键词: Acute; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Cells; Chronic; Critical Care; Data; Dose; Endotoxemia; Endotoxins; Environment; Excision; Gene Expression; Genes; Goals; Health; Human; Immune; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Mediating; Medicine; Modeling; Molecular; Mus; Natural Immunity; Obesity; Outcome; PI3K/AKT; Pathway interactions; Patients; Play; Prevention; Process; Reporting; Risk; Risk Factors; Role; Sepsis; Sepsis Syndrome; Septic Shock; Severities; Shock; Signal Transduction; TLR4 gene; Testing; Trauma; base; chromatin remodeling; conditioning; dosage; effective therapy; human IRAK1 protein; in vivo; interest; macrophage; mortality; novel; prevent; promoter; therapeutic development

DESCRIPTION (provided by applicant): Priming of innate immunity by low grade inflammation is associated with elevated risks of severe systemic inflammatory response syndrome (SIRS) accompanying disseminated endotoxemia, infection and shock. SIRS presents daunting challenges to critical care medicine due to its high mortality risk. Despite its significant health concerns, no effective treatment is currently available. The lack of clear understanding with regard to the underlying molecular mechanisms is the pressing issue. Priming and pre-conditioning of immune environment is believed to be a major risk factor dictating the outcome of septic shock, a process often referred as a second- hit phenomenon. Humans with adverse conditions such as chronic infections, obesity, and aging tend to have subclinical levels of circulating endotoxin, as well as elevated risks for severe septic shock. We demonstrate that subclinical super low levels of endotoxin can effectively prime innate macrophages for a more robust pro- inflammatory response when challenged with a second high dose LPS. Mechanistically, we reported that IRAK- 1 is essential for the pro-inflammatory priming of macrophages by super low dose LPS through removal of the transcriptional suppressor RelB. Pathologically, mice with a prior-hit of super low dose endotoxin have increased mortality when challenged with a second-hit of high dose endotoxin or CLP sepsis. The priming effect is not observed in IRAK-1 deficient mice. Our key objective is to define the molecular mechanisms responsible for the priming of innate immunity. The long term goal is to facilitate the effective prevention and management of acute septic shock. Our key hypothesis is that low-grade endotoxemia increases septic shock risks by priming innate immunity through IRAK-1 mediated modulation of RelB. To test this hypothesis, we plan to perform the following studies. Aim 1 will characterize the molecular mechanisms responsible for the removal of transcriptional suppressor RelB from pro-inflammatory gene promoters by super low dose LPS. Aim 2 will define the unique upstream pathway responsible for the priming of macrophages by super low dose LPS. Aim 3 will examine the in vivo pathological consequences and mechanisms of super low dose priming. Completion of this project will reveal critical mechanisms responsible for innate immunity priming, and contribute to effective prevention and treatment of SIRS accompanying shock and trauma.

描述（由申请人提供）：由低度炎症引发的先天免疫与伴随播散性内毒素血症、感染和休克的严重全身炎症反应综合征（SIRS）风险升高相关。由于其高死亡率风险，SIRS 给重症监护医学带来了严峻的挑战。尽管其健康状况显着 担心，目前没有有效的治疗方法。对潜在分子机制缺乏清晰的了解是紧迫的问题。免疫环境的启动和预调节被认为是决定感染性休克结果的主要危险因素，这一过程通常被称为二次打击现象。患有慢性感染、肥胖和衰老等不利条件的人类往往具有亚临床水平的循环内毒素，并且严重感染性休克的风险较高。我们证明，亚临床超低水平的内毒素可以有效地启动先天巨噬细胞，当受到第二次高剂量 LPS 的攻击时，产生更强烈的促炎反应。从机制上讲，我们报告说，IRAK-1 对于超低剂量 LPS 通过去除转录抑制因子 RelB 启动巨噬细胞促炎至关重要。从病理学角度来看，先前接受过超低剂量内毒素打击的小鼠在接受第二次高剂量内毒素打击或 CLP 败血症时死亡率会增加。在 IRAK-1 缺陷小鼠中未观察到启动效应。我们的主要目标是确定引发先天免疫的分子机制。长期目标是促进急性感染性休克的有效预防和管理。我们的关键假设是，低度内毒素血症通过 IRAK-1 介导的 RelB 调节来启动先天免疫，从而增加感染性休克的风险。为了检验这一假设，我们计划进行以下研究。目标 1 将描述超低剂量 LPS 从促炎基因启动子上去除转录抑制因子 RelB 的分子机制。目标 2 将定义负责通过超低剂量 LPS 启动巨噬细胞的独特上游途径。目标 3 将研究超低剂量启动的体内病理后果和机制。该项目的完成将揭示先天免疫启动的关键机制，并有助于有效预防和治疗伴随休克和创伤的SIRS。

项目成果

Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis.

• DOI: 10.1038/srep34672
• 发表时间: 2016-10-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Diao N;Zhang Y;Chen K;Yuan R;Lee C;Geng S;Kowalski E;Guo W;Xiong H;Li M;Li L
• 通讯作者: Li L