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: 10462644
• 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/10462644
• 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; antagonist; 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)是美国儿童获得性心脏病的主要原因，是一种急性 原因不明的发热性疾病和系统性血管炎，可导致冠状动脉动脉瘤(CAA)和 会导致长期的心血管后遗症。静脉注射免疫球蛋白(IVIG)可降低CAA 发展到5%，高达20%的KD患者对IVIG具有抵抗力，患冠状动脉病变的风险更高 发炎。进一步了解KD发病的免疫病理机制 脉管炎是最重要的研究重点之一。最新的遗传数据，以及来自实验小鼠模型的数据 都集中在IL-1信号在KD皮损发病机制中的关键作用。两个临床病例 使用IL-1R拮抗剂的试验最近在IVIG无效的KD患者中启动。研究 确定参与IL-1β产生的潜在免疫特异性机制是必要的，而且几乎不需要 已知在KD血管炎期间，哪些免疫细胞亚群会产生IL-1β。通过使用KD的小鼠模型 我们发现，与冠状动脉炎症和腹主动脉瘤发展相关的脉管炎 炎症的血管病变是由表达高水平IL1b、Nlrp3的中性粒细胞和嗜酸性粒细胞渗透的 和PADI4转录本，后者编码PAD4，PAD4是一种蛋白质，以其在中性粒细胞外的关键作用而闻名 陷阱(网)编队。我们的初步数据还表明，PAD4抑制不仅能阻断IL-1β 体外生产还可预防LCWE诱导的体内KD血管炎，这种阻断如何直接影响NETs 嗜酸性粒细胞胞外陷阱(EETs)的形成及其IL-1β的产生尚不清楚。我们的新数据 也证明了IL-33是致病的，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，由此得出的中心假设 应用是激活的中性粒细胞和嗜酸性粒细胞通过一种途径促进LCWE诱导的KD血管炎 依赖PAD4释放Net和EET、生物活性IL-1β和其他促炎介质。这里, 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干预措施 目的是阻断这些细胞产生IL-1β和PAD4信号，以及干扰IL-33信号 对嗜酸性粒细胞，这可能会导致炎症减少和防止KD皮损。来调查这件事 中心假设，我们提出了以下具体目标：1)确定浸润性中性粒细胞的作用 在LCWE诱导的KD血管炎过程中，2)确定组织浸润性嗜酸性粒细胞在 3)测定PAD4在中性粒细胞和嗜酸性粒细胞中的作用。 LCWE诱导的KD小血管炎模型。这些研究的成功结束将极大地改变KD的方式 理解并影响新疗法的发展。