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

• 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
• 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

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）是美国儿童获得心脏病的主要原因，是急性 引起冠状动脉瘤（CAA）的未知病因的高热疾病和全身血管炎（CAA）可以 导致长期心血管后遗症。而静脉免疫球蛋白（IVIG）治疗降低CAA 发展到5％，多达20％的KD患者具有IVIG耐药性，并且具有更大的冠状动脉风险 炎。更好地了解导致KD发展的免疫机制 血管炎是最高的研究重点之一。最近的遗传数据和实验小鼠模型的数据 KD的均汇聚在IL-1信号在KD病变的发病机理中的关键作用。两个临床 最近在对IVIG反应的KD患者中启动了使用IL-1R拮抗剂的试验。研究 确定IL-1β产生涉及的潜在免疫特异性机制，几乎没有IS 知道在KD血管炎期间哪种免疫细胞子集产生IL-1β。通过使用KD的鼠模型 与冠状动脉感染和腹主动脉瘤发育相关的血管炎，我们发现 发炎的血管病变被嗜中性粒细胞和嗜酸性粒细胞浸润 和PADI4转录本，后者编码PAD4，这是一种以中性粒细胞外的至关重要的作用而闻名的蛋白质 陷阱（网）形成。我们的初步数据还表明，PAD4抑制不仅是IL-1β 在体外生产，但也可以防止LCWE诱导的KD血管炎在体内，这种阻滞如何直接影响网 嗜酸性粒细胞外陷阱（EET）形成及其IL-1β的产生尚不清楚。我们的新数据 还证明IL-33是致病性的，可以促进嗜酸性粒细胞的促炎功能 通过IL-33受体ST2。因此，基于我们的初步数据，从中的中心假设 应用是激活的中性粒细胞和嗜酸性粒细胞通过A促进LCWE诱导的KD血管炎 PAD4依赖性网络和EET，生物活性IL-1β和其他促炎性介体的释放。这里， 我们将研究嗜酸性粒细胞和中性粒细胞在鼠KD血管炎和建议干预措施中的作用 旨在阻止这些细胞和PAD4信号传导的IL-1β以及IL-33信号的破坏 关于嗜酸性粒细胞，这可能导致感染减少和预防KD病变。调查这一点 中心假设，我们提出以下特定目的：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 LCWE诱导的KD血管炎。这些研究的成功结论将大大改变KD的方式 了解和影响新疗法的发展。