Inflammasome Danger Signaling:A Novel Target to Prevent Debris Induced Osteolysis

炎性体危险信号：预防碎片引起的骨溶解的新靶点

• 批准号: 8666518
• 负责人: Nadim James Hallab
• 金额: $ 30.36万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666518
• 关键词: Accounting; Address; Adjuvant; Age-Years; Animal Model; Antigen-Presenting Cells; Arthroplasty; Calvaria; Caspase-1; Cell Culture Techniques; Cytosol; Data; Effectiveness; Elderly; Failure; Goals; Healthcare; Hip region structure; IL8 gene; Immune; Immune response; Immune system; Immunohistochemistry; Implant; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Intervention; Joints; Knee; Knowledge; Lead; Life; Longevity; Mediating; Metals; Modeling; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; Operative Surgical Procedures; Osteolysis; Particulate; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacotherapy; Production; Publishing; Replacement Arthroplasty; Reporting; Signal Pathway; Signal Transduction; Sterility; Stress; TNF gene; Testing; Tissues; United States; Vaccines; Work; base; clinically relevant; cohort; cost; cytokine; design; effective therapy; extracellular; human subject; in vivo; inhibitor/antagonist; insight; macrophage; monocyte; mortality; novel; particle; pathogen; prevent; protein complex; public health relevance; response; survivorship; translational study; treatment strategy

DESCRIPTION (provided by applicant): All of the > one million total joint replacements/year that are performed in the United States are expected to eventually fail if their recipients live log enough, due to implant debris induced inflammatory responses. This is particularly troubling for millions of elderly people who may need a revision in their last decades of life where the incidence of mortality of major surgery can be as high as 13% (vs. <1% in patients <75 years of age). Non-surgical treatments to extend implant life are currently unavailable. Debris induced inflammation is well known to induce local innate immune responses, i.e. monocytes/macrophages activate NF and secretion of IL-1, TNF, IL-6 and IL-8 resulting in localized inflammation. However, implant debris are sterile, relatively inert, and do not present the molecular patterns of a typical pathogen. So, how do extra- and intracellular mechanisms sense and respond to exogenous non-biological challenge agents such as implant debris? Recent progress points to the involvement of the "inflammasome", a danger signaling pathway. Our recently published initial findings on implant debris-induced inflammasome activation provide an important insight into this pathway that can sense stress and danger signals triggered by contact with certain non-biological challenge agents, including particulate adjuvants present in modern vaccines. These results suggest that inflammasome danger signaling is central to potentiating innate macrophage-based responses to implant debris (i.e. from initial lysosomal destabilization and NADPH oxidase induction of ROS, to NALP3-ASC oligomerization, and Caspase 1 conversion of pro-IL-1 to IL-1. Our long term goal is to understand how to manipulate the inflammasome pathway to mitigate the untoward effects of implant debris. The objective of this proposal is to determine both the utility of this approach an how best to mitigate implant debris induced osteolysis. Several key questions are: 1) what component(s) of the inflammasome pathway are best targeted to reduce debris-mediated inflammation? 2) Can inhibition of debris induced inflammasome activation lead to decreased aseptic osteolysis in vivo, i.e. is it a viable target for pharmacotherapy? 3) Does debris induced inflammasome activation preferentially occur in people with debris-induced aseptic osteolysis? We propose to examine these three questions under the following central hypothesis. We hypothesize that implant debris induced inflammasome danger signaling is central to implant debris immune reactivity and blocking this response is an effective means to mitigate implant debris induced aseptic osteolysis. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following three specific aims. Specific Aim 1 is to determine, whether clinically available inflammasome-specific drugs are as effective in preventing general macrophage inflammatory responses vs. other (non-clinical) inflammasome-pathway-specific inhibitors and if lysosomal destabilization is critical for the initiation of debrs-induced inflammasome activation. Specific Aim 2 is to determine the effect of blocking the inflammasome pathway on particle induced inflammation and aseptic wear debris-induced osteolysis using an established animal model. Specific Aim 3 is to determine the clinical relevance of treating debris-induced inflammation by blocking the inflammasome pathway. We will test the effectiveness of selective inflammasome inhibition on wear debris-induced pro-inflammatory cytokine production by primary monocyte/macrophage cultures from arthroplasty cohorts, and determine if these effects correlate with inflammasome activity in peri-implant tissues determined by quantitative immunohistochemistry and tissue cytokine expression. This translational study will determine if inflammasome danger signaling activation to implant debris is an effective new target for pharmacologically addressing aseptic osteolysis. We expect to substantially forward our understanding of how sterile non-biological implant debris actually induces an immune system response that leads to aseptic osteolysis. Such results will provide a positive impact and potentially powerful treatment for millions of people with implants, particularly those over 75 years of age, who may be able to block implant debris associated osteolysis, postponing indefinitely the associated morbidity and mortality of revision total joint replacement surgery.

描述（由申请人提供）：由于植入物碎片诱导的炎症反应，如果接受者的存活时间足够长，预计美国每年进行的所有> 100万例关节置换术最终都会失败。这对于数百万老年人来说尤其令人不安，他们可能需要在生命的最后几十年进行翻修，其中大手术的死亡率可能高达13%（而<75岁的患者<1%）。目前还没有延长植入物寿命的非手术治疗方法。碎片诱导的炎症众所周知会诱导局部先天性免疫应答，即单核细胞/巨噬细胞激活NF并分泌IL-1、TNF、IL-6和IL-8，导致局部炎症。然而，植入物碎片是无菌的、相对惰性的，并且不呈现典型病原体的分子模式。那么，细胞外和细胞内机制如何感知和响应外源性非生物挑战剂，如植入物碎片？最近的进展指出了“炎性体”的参与，这是一种危险信号通路。我们最近发表的关于植入物碎片诱导的炎性小体激活的初步研究结果为这一途径提供了重要的见解，该途径可以感知与某些非生物激发剂接触引发的压力和危险信号，包括现代疫苗中存在的颗粒佐剂。这些结果表明，炎性小体危险信号传导对于增强对植入物碎片的先天性基于巨噬细胞的反应（即，从初始溶酶体去稳定化和ROS的NADPH氧化酶诱导，到NALP 3-ASC寡聚化，以及pro-IL-1到IL-1的半胱天冬酶1转化）是至关重要的。我们的长期目标是了解 如何操纵炎性体通路以减轻植入物碎片的不良影响。本提案的目的是确定该方法的实用性以及如何最好地缓解植入物碎片诱导的骨质溶解。几个关键问题是：1）炎性体途径的哪些组分最能减少碎片介导的炎症？2)抑制碎片诱导的炎性小体活化是否能减少体内无菌性骨质溶解，即它是否是药物治疗的可行靶点？3)碎片诱导的炎性小体激活是否优先发生在碎片诱导的无菌性骨质溶解患者中？我们建议在以下中心假设下研究这三个问题。我们假设植入物碎片诱导的炎性体危险信号是植入物碎片免疫反应的核心，阻断这种反应是减轻植入物碎片诱导的无菌性骨质溶解的有效手段。我们计划通过追求以下三个具体目标来测试我们的中心假设并实现本申请的目标。具体目的1是确定临床上可用的炎性体特异性药物在预防一般巨噬细胞炎症反应方面是否与其他（非临床）炎性体途径特异性抑制剂一样有效，以及溶酶体不稳定是否对碎片诱导的炎性体活化的启动至关重要。具体目标2是使用已建立的动物模型确定阻断炎性体通路对颗粒诱导的炎症和无菌磨损碎屑诱导的骨质溶解的影响。具体目标3是确定通过阻断炎性体途径治疗碎片诱导的炎症的临床相关性。我们将通过来自关节成形术队列的原代单核细胞/巨噬细胞培养物测试选择性炎性小体抑制对磨损碎屑诱导的促炎性细胞因子产生的有效性，并通过定量免疫组织化学和组织细胞因子表达确定这些效应是否与植入物周围组织中的炎性小体活性相关。这项转化研究将确定炎性小体危险信号激活植入物碎片是否是治疗无菌性骨质溶解的有效新靶点。我们希望能够进一步了解无菌非生物植入物碎片实际上如何诱导免疫系统反应，导致无菌性骨质溶解。这些结果将为数百万植入物的患者提供积极的影响和潜在的强大治疗，特别是那些75岁以上的患者，他们可能能够阻止植入物碎片相关的骨质溶解，无限期推迟翻修全关节置换手术的相关发病率和死亡率。