Mechanisms of NLRC4 inflammasome-associated hyperinflammation

 描述(申请人提供)：长期以来，人们一直认为，失调的炎症会导致许多人类疾病。全身性炎症反应与感染(称为脓毒症)最相关，是一种常见的、危及生命的高炎性损伤。关于是什么调节适当的炎症反应和过度的炎症反应，或者如何操纵炎症以防止损害，人们知之甚少。这项建议的目标是了解一种名为NLRC4的蛋白质的突变是如何导致一种名为巨噬细胞激活综合征(MAS)的人类脓毒症样表型的。当NLRC4被激活时，它会触发一个称为炎症体的大型蛋白质复合体的形成。炎症小体通过激活促炎细胞因子和诱导炎症形式的细胞死亡来推动全身炎症。有趣的是，除了MAS，NLRC4突变还会导致早发性肠炎，这种炎症在婴儿时期就会消失。这些突变是如何导致这种特定的高炎症综合征的尚不清楚。了解这一机制将为了解炎症小体的基本功能、高炎症损伤的危险因素、全身炎症的不同免疫“味道”以及我们可能进行干预以防止损害的方法提供重要的见解。该提案的目标1将研究NLRC4突变导致炎症损伤的机制。为了促进这一点，NLRC4的突变将与一种名为NLRP3的相关炎症体成分的突变进行比较。NLRP3的过度活动也会导致炎症小体的形成，但这是一种非常不同的炎症综合征。这个目标将集中在这些不同的炎性小体如何在同一种细胞类型中发挥作用，以及哪些细胞具有活跃的炎性小体的全身性影响。肠上皮细胞中炎性小体的独特作用可能是NLRC4-MAS特有的瞬时肠道表型。目的2将探索一个重要但神秘的发现：炎症体依赖细胞因子IL-18在MAS中异常和慢性升高(与NLRC4突变无关)，但不是NLRP3相关疾病。这一目标将研究长期暴露在高IL-18下如何启动免疫系统，使其对危险信号做出类似MAS的反应，系统地和深入地观察IL-18反应细胞。完成这些目标，再加上本提案所包括的培训机会，将为独立翻译调查员的职业生涯奠定必要的基础。

 DESCRIPTION (provided by applicant): It has long been recognized that dysregulated inflammation causes many human diseases. The systemic inflammatory response, best associated with infections (termed sepsis), is a common and life- threatening example of hyperinflammatory damage. Very little is known about what regulates an appropriate versus excessive inflammatory response, or how to manipulate inflammation to prevent damage. The goal of this proposal is to understand how mutations in a protein called NLRC4 result in a human sepsis-like phenotype known as Macrophage Activation Syndrome (MAS). When activated, NLRC4 triggers the formation of a large protein complex called the inflammasome. Inflammasomes drive inflammation throughout the body by activating pro-inflammatory cytokines and inducing an inflammatory form of cell death. Intriguingly, in addition to MAS, NLRC4 mutations cause early-onset intestinal inflammation that resolves in infancy. How these mutations result in this specific hyperinflammatory syndrome is unknown. Understanding this mechanism will provide important insights into basic inflammasome function, the risk factors for hyperinflammatory damage, the different immunologic "flavors" of systemic inflammation, and the ways we might intervene to prevent damage. Aim 1 of this proposal will examine the mechanisms by which NLRC4 mutations cause inflammatory damage. To facilitate this, NLRC4 mutations will be compared to mutations in a related inflammasome component called NLRP3. NLRP3 hyperactivity also causes inflammasome formation, but a very different inflammatory syndrome. This aim will focus on how these different inflammasomes function in the same cell type, as well as the systemic effects of which cells have active inflammasomes. The unique role of inflammasomes in intestinal epithelial cells may inform the transient gut phenotype unique to NLRC4-MAS. Aim 2 will explore an important but enigmatic finding: extraordinary and chronic elevation of the inflammasome- dependent cytokine IL-18 occurs in MAS (regardless of NLRC4 mutations) but not NLRP3-related diseases. This aim will examine how chronic exposure to high IL-18 primes the immune system for an MAS-like response to danger signals, looking both systemically and in-depth at IL-18 responsive cells. Completion of these aims, along with the training opportunities included as part of this proposal, will establish the necessary foundation for a career as an independent translational investigator.