Macrophage inflammasome regulation

项目摘要/摘要： 最近的一项发现加强了先天免疫在肺部抵御病原体方面的重要性 不同的细胞内病原体识别受体，检测病原体进入细胞质的途径 巨噬细胞。这些受体包括NOD样受体(NLR)以及NOD非依赖性感受器，如 就像吡喃一样。细胞内感应器的一个关键功能是直接调节caspase-1酶。 通过一种名为炎症体的蛋白质调节复合体。在炎症室里，NLR和点头 独立的传感器通过比林结构域(PYD)或半胱氨酸天冬氨酸氨基转移酶(Caspase)募集与接头蛋白ASC相互作用 域(卡)。这种相互作用诱导了caspase-1的二聚化和自动激活。然后是caspase-1 激活IL-1的前体β和IL-18，而激活的caspase-1也驱动一种形式的细胞死亡 巨噬细胞和淋巴细胞称为上睑下垂。这些事件被强烈地与 炎症性肺部疾病，如肺纤维化。然而，尽管提供了概念上的进步 炎症组的发现，这个复合体是如何组装和控制的仍然模糊不清，限制了我们的 了解肺部炎症和我们创造新疗法的能力。在这方面，目前 应用程序试图通过将其结构和功能与快速反应相联系来扩展炎症小体假说 涉及酪氨酸酶活性的事件。我们的初步数据表明，吡喃是一种关键的 炎性小体的成分。我们证明了吡喃具有将酪氨酸激酶带到 炎症体复合体通过其磷酸化来调节ASC的功能。因此，我们假设 这些与吡喃相关的活性可以通过磷酸化促进asc和caspase-1之间的相互作用。 在ASC的卡域中的保守酪氨酸中。此外，我们还发现，常住肺泡 巨噬细胞与炎性巨噬细胞的不同之处在于它们对吡喃的相对表达。 利用这些关键发现，该项目提出了以下具体目标：1)剖析 磷酸化在ASC炎症小体调节中的作用；2)确定吡喃在调节ASC中的作用 依赖于磷酸化的人炎性小体激活；以及3)发现关键的调控途径 人肺泡巨噬细胞和慢性支气管炎患者外周血巨噬细胞caspase-1活性的比较 特发性肺纤维化(IPF)，以了解是否存在吡喃和ASC依赖的炎症体信号事件的差异。 该项目的成功完成表明，该项目有望为炎症性疾病提供新的治疗目标 肺部疾病。

Project Summary/Abstract: Innate immunity’s importance in lung defense against pathogens has been heightened by the recent discovery of distinct intracellular pathogen recognition receptors that detect pathogen access to the cytosol of macrophages. These receptors include NOD-like receptors (NLRs) as well as NOD independent sensors such as pyrin. A critical function of the intracellular sensors is their direct regulation of the enzyme caspase-1 through a protein regulatory complex called an inflammasome. In an inflammasome, NLRs and NOD independent sensors interact with an adaptor protein ASC via pyrin domains (PYD) or caspase recruitment domains (CARD). This interaction induces caspase-1 dimerization and auto-activation. Caspase-1 then activates the precursors of IL-1β and IL-18, and active caspase-1 also drives a form of cell death of macrophages and lymphocytes known as pyroptosis. These events have been strongly associated with inflammatory lung disorders like pulmonary fibrosis. However, despite the conceptual advances provided by the inflammasome discovery, how this complex is assembled and controlled remains obscure, limiting our understanding of lung inflammation and our ability to create new therapies. In this context, the present application seeks to expand upon the inflammasome hypothesis by linking its structure and function to rapid events that involve tyrosine kinase activities. Our preliminary data point to a role for pyrin as a critical component of inflammasomes. We show that pyrin has the capacity to bring tyrosine kinases to the inflammasome complex to modulate ASC’s function via its phosphorylation. We therefore hypothesize that these pyrin-affiliated activities can promote interactions between ASC and caspase-1 via phosphorylations within conserved tyrosines in the CARD domains of ASC. Furthermore, we have found that resident alveolar macrophages differ from inflammatory macrophages in accordance with their relative expressions of pyrin. Utilizing these key discoveries, the project proposes the following specific aims, 1) to dissect the role of phosphorylation in ASC inflammasome regulation; 2) to determine pyrin’s role in modulating ASC phosphorylation dependent human inflammasome activation; and 3) to uncover critical pathways regulating caspase-1 activation by comparing resident human alveolar macrophage and macrophages from patients with idiopathic pulmonary fibrosis (IPF) for differences in pyrin and ASC dependent inflammasome signaling events. The successful completion of this project shows promise to provide new treatment targets for inflammatory lung disorders.