Mechanisms of NLRC4 inflammasome-associated hyperinflammation

 描述（由申请人提供）：长期以来，人们已经认识到失调的炎症导致许多人类疾病。与感染最相关的全身性炎症反应（称为脓毒症）是炎症过度损伤的常见且危及生命的实例。关于是什么调节适当的炎症反应还是过度的炎症反应，或者如何操纵炎症以防止损伤，我们知之甚少。该提案的目标是了解一种名为NLRC 4的蛋白质突变如何导致称为巨噬细胞激活综合征（MAS）的人类败血症样表型。 当被激活时，NLRC 4触发一种称为炎性体的大型蛋白质复合物的形成。炎性小体通过激活促炎细胞因子和诱导细胞死亡的炎性形式来驱动全身的炎症。有趣的是，除了MAS，NLRC 4突变会导致早发性肠道炎症，并在婴儿期消退。这些突变如何导致这种特定的炎症反应过度综合征尚不清楚。了解这一机制将提供重要的见解基本炎症体功能，高炎症损伤的危险因素，不同的免疫“风味”的全身性炎症，以及我们可以干预，以防止损害。 本提案的目的1将研究NLRC 4突变引起炎症损伤的机制。为了促进这一点，NLRC 4突变将与称为NLRP 3的相关炎性体组分中的突变进行比较。NLRP 3过度活跃也会导致炎性小体形成，但这是一种非常不同的炎性综合征。这个目标将集中在这些不同的炎性小体如何在相同的细胞类型中发挥作用，以及哪些细胞具有活性炎性小体的全身效应。炎性小体在肠上皮细胞中的独特作用可以告知NLRC 4-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：炎性小体依赖性细胞因子IL-18的异常和慢性升高发生在MAS中（无论NLRC 4突变如何），而不是NLRP 3相关疾病。这个目标将研究长期暴露于高IL-18如何引发免疫系统对危险信号的MAS样反应，系统性和深入地观察IL-18反应细胞。这些目标的完成，沿着培训机会，包括作为本提案的一部分，将建立作为一个独立的翻译研究者的职业生涯的必要基础。

 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.