Role of neutrophils and eosinophils in bacterial ligand-induced vasculitis

中性粒细胞和嗜酸性粒细胞在细菌配体诱导的血管炎中的作用

基本信息

批准号：
10269029
负责人：
Moshe Arditi
金额：
$ 58.24万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269029
关键词：
Abdomen Acute Affect Alternative Therapies Aneurysm Animal Model Aortic Aneurysm Aortitis Arteritis Blood Vessels Cardiovascular system Cell Wall Cells Child Childhood Chronic Clinical Trials Coronary Coronary artery Cytokine Signaling Data Development Disease Disease model Etiology Family Fever Gene Expression Genetic Heart Diseases Histologic Human Immune Immunoglobulin G Immunologics In Vitro Incidence Inflammasome Inflammation Inflammation Mediators Inflammatory Innate Immune Response Interleukin-1 Interleukin-1 beta Intervention Intravenous Immunoglobulins Lactobacillus casei Lead Lesion Ligands Maps Modeling Monoclonal Antibodies Mucocutaneous Lymph Node Syndrome Mus Myocarditis Neutrophilic Infiltrate Pathogenesis Pathogenicity Pathologic Pathology Patients Prevention Prevention approach Production Proteins Research Priority Resistance Risk Role Serine Protease Severities Signal Transduction Testing Tissue Sample Tissues Transcript Vasculitis abdominal aorta anakinra animal data base coronary arteritis cytokine eosinophil experimental study extracellular in vivo infection risk member mouse model neutrophil new therapeutic target novel strategies novel therapeutics prevent receptor vascular inflammation vascular injury

项目摘要

PROJECT ABSTRACT Kawasaki disease (KD), the leading cause of acquired heart disease among children in the US, is an acute febrile illness and systemic vasculitis of unknown etiology that causes coronary artery aneurysms (CAA) and can result in long-term cardiovascular sequelae. While Intravenous immunoglobulin (IVIG) treatment lowers CAA development to 5%, up to 20% of KD patients are IVIG-resistant and have a greater risk for coronary inflammation. A better understanding of the immune pathological mechanisms leading to the development of KD vasculitis is one of the highest research priorities. Recent genetic data, and data from experimental mouse model of KD, have all converged on the critical role of IL-1 signaling in pathogenesis of the KD lesions. Two clinical trials using the IL-1R antagonist were recently initiated in KD patients who do not respond to IVIG. Studies identifying the underlying immune-specific mechanisms involved in IL-1β production are needed and little is known regarding which immune cell subsets produce IL-1β during KD vasculitis. By using a murine model of KD vasculitis associated with coronary artery inflammation and abdominal aorta aneurysm development, we found that inflamed vascular lesions are infiltrated by neutrophils and eosinophils that express high levels of Il1b, Nlrp3 and Padi4 transcripts, the latter one encodes PAD4, a protein known for its crucial role in neutrophils extracellular traps (NETs) formation. Our preliminary data also demonstrate that PAD4 inhibition blocks not only IL-1β production in vitro but also prevents LCWE-induced KD vasculitis in vivo, how this blockade directly affect NETs and eosinophils extracellular traps (EETs) formation and their IL-1β production remain unknown. Our new data also demonstrate that IL-33 is pathogenic and may promote the pro-inflammatory functions of eosinophils through the IL-33 receptor, ST2. Therefore, based on our preliminary data, the central hypothesis from this application is that activated neutrophils and eosinophils promote LCWE-induced KD vasculitis through a PAD4-dependent release of NETs and EETs, bioactive IL-1β and other pro-inflammatory mediators. Here, we will investigate the role of eosinophils and neutrophils during murine KD vasculitis and propose interventions aiming to block IL-1β production by those cells and PAD4 signaling, as well as the disruption of IL-33 signaling on eosinophils, which may result in decreased inflammation and the prevention of KD lesions. To investigate this central hypothesis, we propose the following specific aims: 1) Determine the role of infiltrating neutrophils during LCWE-induced KD vasculitis, 2) Determine the role of tissue-infiltrating eosinophils during LCWE-induced KD vasculitis and 3)Determine the role of PAD4 in neutrophils and eosinophils during LCWE-induced KD vasculitis. The successful conclusion of these studies will significantly alter the way KD is understood and influence the development of new therapies.

项目摘要川崎病 (KD) 是美国儿童获得性心脏病的主要原因，是一种急性病因不明的发热性疾病和系统性血管炎，可导致冠状动脉瘤 (CAA)，并可导致长期心血管后遗症，而静脉注射免疫球蛋白 (IVIG) 治疗可降低 CAA。发展至 5%，高达 20% 的 KD 患者对 IVIG 耐药，且冠状动脉风险更大更好地了解导致川崎病发生的免疫病理机制。血管炎是最近的研究重点之一，数据来自实验小鼠模型。 KD 的两个临床研究都集中在 IL-1 信号传导在 KD 病变发病机制中的关键作用。最近在对 IVIG 研究无反应的川崎病患者中启动了使用 IL-1R 拮抗剂的试验。需要确定参与 IL-1β 产生的潜在免疫特异性机制，但目前所做的工作很少通过使用 KD 小鼠模型，了解哪些免疫细胞亚群在 KD 血管炎期间产生 IL-1β。我们发现，血管炎与冠状动脉炎症和腹主动脉瘤的发展有关发炎的血管病变被表达高水平 Il1b、Nlrp3 的中性粒细胞和嗜酸性粒细胞浸润和 Padi4 转录本，后者编码 PAD4，一种因其在中性粒细胞胞外中发挥关键作用而闻名的蛋白质我们的初步数据还表明，PAD4 抑制不仅能阻断 IL-1β。体外生产，还可以预防体内 LCWE 诱导的 KD 血管炎，这种封锁如何直接影响 NET 嗜酸性粒细胞胞外陷阱 (EET) 的形成及其 IL-1β 的产生仍然未知。还证明 IL-33 具有致病性，并可能促进嗜酸性粒细胞的促炎功能通过 IL-33 受体 ST2 因此，根据我们的初步数据，中心假设由此而来。应用是激活的中性粒细胞和嗜酸性粒细胞通过以下方式促进 LCWE 诱导的 KD 血管炎： PAD4 依赖性释放 NET 和 EET、生物活性 IL-1β 和其他促炎介质。我们将研究嗜酸性粒细胞和中性粒细胞在小鼠 KD 血管炎中的作用并提出建议旨在阻断这些细胞产生 IL-1β 和 PAD4 信号传导，以及破坏 IL-33 信号传导嗜酸性粒细胞，这可能会减少炎症并预防 KD 病变。中心假设，我们提出以下具体目标：1）确定浸润性中性粒细胞的作用在 LCWE 诱导的 KD 血管炎期间，2) 确定组织浸润性嗜酸性粒细胞在 LCWE诱导的KD血管炎和3)确定PAD4在中性粒细胞和嗜酸性粒细胞中的作用这些研究的成功结论将显着改变 LCWE 诱发的 KD 血管炎。了解并影响新疗法的开发。