Innate priming in sepsis exacerbation

描述（由申请方提供）：低度炎症引发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SIRS的高死亡率风险，其对重症监护医学提出了严峻的挑战。尽管它的健康状况 然而，目前还没有有效的治疗方法。对潜在的分子机制缺乏明确的理解是一个紧迫的问题。免疫环境的引发和预调节被认为是决定败血性休克结果的主要风险因素，败血性休克是一种通常被称为二次打击现象的过程。患有慢性感染、肥胖和衰老等不良疾病的人往往具有亚临床水平的循环内毒素，以及严重脓毒性休克的风险升高。我们证明，亚临床超低水平的内毒素可以有效地引发先天性巨噬细胞，当用第二高剂量LPS攻击时，产生更强烈的促炎反应。从机制上讲，我们报道了IRAK- 1是通过去除转录抑制因子RelB而由超低剂量LPS引发巨噬细胞的促炎性启动所必需的。在病理学上，当用高剂量内毒素或CLP脓毒症的第二次攻击时，具有超低剂量内毒素的先前攻击的小鼠具有增加的死亡率。在IRAK-1缺陷型小鼠中未观察到引发效应。我们的主要目标是确定负责启动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。我们的主要假设是，低度内毒素血症通过IRAK-1介导的RelB调节引发先天免疫，从而增加感染性休克的风险。为了验证这一假设，我们计划进行以下研究。目的1研究超低剂量LPS对促炎基因启动子区转录抑制因子RelB的去除机制。目的2将确定超低剂量LPS引发巨噬细胞的独特上游途径。目的3：研究超低剂量预充的体内病理后果及其机制。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。

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.