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）：低年级炎症对先天免疫的启动与伴随传播性内毒素，感染和冲击的严重全身性炎症综合征（SIR）的风险升高有关。 Sirs由于其高死亡率风险，提出了对重症监护医学的艰巨挑战。尽管健康状况很高 担心，目前没有有效的治疗方法。关于潜在的分子机制缺乏明确的理解是紧迫的问题。据信，免疫环境的启动和预处理是决定败血性休克结果的主要危险因素，这一过程通常被称为第二次命中现象。慢性感染，肥胖和衰老等不利条件的人倾向于具有亚临床水平的循环内毒素，以及严重败血性休克的风险升高。我们证明，当用第二个高剂量LP挑战时，亚临床超低水平的内毒素可以有效地给先天性巨噬细胞产生更强的促炎反应。从机械上讲，我们报道说，通过去除转录抑制器RELB，IRAK-1对于通过超低剂量LPS​​促巨噬细胞的促疾病至关重要。从病理上讲，当用第二次高剂量内毒素或CLP败血症挑战时，具有超低剂量内毒素的先前打击的小鼠死亡率增加。在IRAK-1缺乏小鼠中未观察到启动效应。我们的主要目标是定义负责先天免疫力启动的分子机制。长期目标是促进有效的预防和管理急性败血性冲击。我们的主要假设是，低度内毒素血症通过通过IRAK-1介导的RERB调节来启动先天免疫来增加败血性休克风险。为了检验这一假设，我们计划进行以下研究。 AIM 1将表征负责通过超低剂量LPS​​从促炎基因启动子中去除转录抑制器的分子机制。 AIM 2将定义由超低剂量LPS​​启动巨噬细胞的独特上游途径。 AIM 3将检查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负责先天免疫启动的关键机制，并有助于预防和治疗伴随冲击和创伤的先生。

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