How cell death and sterile particulates stimulate inflammation and disease

描述（由申请人提供）：当细胞在体内死亡并经历坏死时，它们总是会刺激炎症反应。这会对邻近的健康组织造成相当大的附带损害，并被认为是许多急性和慢性疾病发病机制的基础。许多其他颗粒刺激（尿酸盐、二氧化硅、石棉、氧化铁等）也会刺激无菌炎症，从而导致疾病。这项资助的总体目标是阐明死细胞和其他无菌颗粒刺激炎症的机制。在目标1中，我们将定义在体内感知细胞死亡和其他刺激性颗粒刺激并触发急性炎症反应的细胞监视机制。这一目标背后的假设是，先天免疫系统的细胞充当哨兵，监测组织对这些刺激的反应，并在检测到它们时产生IL-1，然后驱动急性炎症反应。这项研究的目的是验证这一假设，并确定参与这一过程的关键细胞类型。我们还将测试这些机制在引起组织损伤和疾病中的作用。我们的第二个目标是阐明细胞生物学和分子途径，通过死细胞和无菌颗粒刺激先天免疫细胞产生IL-1。我们的基本假设是：(i)这些颗粒刺激必须内化到巨噬细胞的吞噬体中；（ii）内化后导致巨噬细胞活化的关键事件是部分吞噬体的破裂；（iii）被激活的吞噬体内容物释放到细胞质中，由nod样受体NLRP3感知；(v)组织蛋白酶是吞噬体释放的激活NLRP3诱导IL-1产生的关键介质。本Aim的目的是检验这些假设。这些假设的重要性在于，它们提供了一个新的、可测试的范式，如果正确的话，将揭示一个共同的统一途径，并确定治疗干预的可处理的分子靶点。

DESCRIPTION (provided by applicant): When cells die in vivo and undergo necrosis they invariably stimulate an inflammatory response. This causes considerable collateral damage to adjacent healthy tissue and is thought to underlie the pathogenesis of a number of acute and chronic diseases. A number of other particulate stimuli (urate, silica, asbestos, iron oxide, etc.) also stimulate sterile inflammation that leads to disease. The overall goal of this grant is to elucidate the mechanisms by which dead cells and other sterile particulates stimulate inflammation. In Aim 1 we will define the cellular surveillance mechanisms in vivo that sense cell death and other irritant particulate stimuli and in response trigger an acute inflammatory response. The hypothesis underlying this Aim is that cells of the innate immune system function as sentinels that monitor tissues for these stimuli and upon detecting them produce IL-1 that then drives the acute inflammatory response. The goal of this aim is to test this hypothesis and to define the key cell types involved in this process. We will also test the role of these mechanisms in causing tissue damage and disease. Our second Aim seeks to elucidate the cell biological and molecular pathways through which dead cells and sterile particulates stimulate innate immune cells to produce IL-1. Our underlying hypotheses are that: (i) These particulate stimuli must be internalized into phagosomes of macrophages; (ii) After internalization the key event that leads to macrophage activation is rupture of some phagosomes; (iii) The resulting release of activated phagosomal contents into the cytosol is sensed by the NOD-like receptor NLRP3; and (v) Cathepsins are the key mediators released from phagosomes that activate NLRP3 to induce IL-1 production. The goal of this Aim is to test these hypotheses. The importance of these hypotheses is that they offer a new and testable paradigm, which if correct will reveal a common unifying pathway and identify tractable molecular targets for therapeutic intervention.