Role of interleukin-3 in autoimmune and viral myocarditis

IL-3 在自身免疫性和病毒性心肌炎中的作用

• 批准号: 10172970
• 负责人: John Edward Mindur
• 金额: $ 0.65万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172970
• 关键词: Acute; Adoptive Transfer; Affect; Amplifiers; Anatomy; Animal Model; Antibody Therapy; Arrhythmia; Attenuated; Autoimmune; Automobile Driving; Basophils; Biological; Biology; Biopsy; CD4 Positive T Lymphocytes; Cardiac; Cardiogenic Shock; Cell Lineage; Cell Separation; Cell physiology; Cells; Characteristics; Chronic; Classification; Clinical; Colony-Stimulating Factors; Complex; Congestive Heart Failure; Coxsackie Viruses; Data; Dendritic Cells; Development; Diagnosis; Dilated Cardiomyopathy; Disease; Disease Outcome; Disease Progression; Family; Fatal Outcome; Fibrosis; Flow Cytometry; Foundations; Genetic; Glean; Guidelines; Heart; Heart Diseases; Heart Hypertrophy; Helper-Inducer T-Lymphocyte; Hematopoietic; Histologic; Histology; Imaging Techniques; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-3 Receptor; Interleukins; Knockout Mice; Leukocytes; Life; Link; Location; Mediating; Modeling; Molecular Biology; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myocardial; Myocarditis; Myocardium; Non-Invasive Cancer Detection; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Play; Process; Production; Receptor Cell; Receptor Signaling; Role; Sepsis; Severities; Shapes; Sudden Death; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Viral Load result; Work; allergic response; base; bone marrow hyperplasia; cardiac muscle disease; cell type; cellular targeting; cytokine; detection method; efficacy evaluation; heart function; in vivo; insight; macrophage; mast cell; monocyte; mortality; mouse model; novel; prevent; progenitor; recruit; stem; targeted treatment; therapeutic target; viral myocarditis

Myocarditis is a heterogeneous inflammatory disease of the heart muscle that constitutes a wide spectrum of inflammatory pathologies. It can manifest from mild subclinical disease to severe outcomes, including cardiogenic shock, life-threatening arrhythmias, and even sudden death. While many patients recover from acute illness associated with myocarditis, the long-term sequelae of myocardial inflammation involves the development of inflammatory dilated cardiomyopathy and chronic heart failure, both for which treatment options are gravely limited. Given that myocarditis is such a highly polymorphic disease and specific clinical guidelines for its treatment do not exist, it is important to identify common underlying mechanisms that drive myocardial inflammation, in order to better prevent morbidity and mortality associated with myocarditis. To-date, most information regarding the pathogenesis of myocarditis has been gleaned from animal models that mimic aspects of autoimmune and viral myocarditis. In these models, CD4+ T cells play a major role in driving inflammation. However, it is still mechanistically unclear how various cytokines produced by these cells can promote myocardial inflammation and disease progression to more serious and fatal outcomes. Interestingly, our preliminary work suggests that interleukin (IL)-3, a cytokine from the colony-stimulating factor (CSF) family, drives inflammation in the heart during the peak of experimental autoimmune myocarditis (EAM). For example, we recently discovered that IL-3-deficient mice are protected from cardiac inflammation in EAM. Upon profiling heart leukocytes, we found that IL-3 is specifically produced by CD4+ T helper (TH) cells at the peak of EAM, and determined that cardiac MHC-II+ macrophages, monocytes, and monocyte-derived dendritic cells (moDC) express the IL-3 receptor (IL-3R) at the peak of EAM, thus identifying these IL-3R+ cells as putative IL-3 responders. Together, these data led us to propose the central hypothesis that IL-3 is essential for driving T cell-mediated cardiac inflammation in myocarditis. Here, I aim to examine IL-3-mediated mechanisms that drive inflammation using two well-characterized mouse models of myocarditis (i.e. EAM and coxsackievirus B3 (CVB3)-induced myocarditis). My specific aims are as follows: (I) I will assess how IL-3:IL-3R signaling modulates leukocyte dynamics in myocarditis in the heart and periphery. (II) I will define the lineage origin and characteristics of IL-3-producing T cells during myocarditis. (III) Finally, I will also evaluate the efficacy of targeting IL-3/IL-3R signaling myocarditis inflammation and disease outcome. Utilizing genetic knockout mice, various in vivo and in vitro analyses, flow cytometry and cell sorting, molecular biology, histology, and imaging techniques, I aim to determine how IL-3:IL-3R signaling shapes leukocyte function, identify subsets T cells that are drivers of IL-3-mediated cardiac inflammation, and uncover biological targets that are therapeutically relevant for ameliorating myocardial inflammation, hindering disease progression, and preventing sudden death.

心肌炎是心肌的异质性炎症性疾病，构成了广泛的疾病 炎症性病理。它可以从轻度亚临床疾病到严重的结果，包括 心源性休克，威胁生命的心律失常，甚至猝死。许多患者从 与心肌炎相关的急性疾病，心肌炎症的长期后遗症涉及 炎症性扩张性心肌病和慢性心力衰竭的发展，既治疗 选项受到严重限制。鉴于心肌炎是一种高度多态疾病和特定的临床疾病 不存在治疗指南，重要的是要确定驱动的常见潜在机制 心肌炎症，以更好地预防与心肌炎相关的发病率和死亡率。 迄今为止，有关心肌炎发病机理的大多数信息已从动物中收集 模仿自身免疫性和病毒心肌炎方面的模型。在这些模型中，CD4+ T细胞发挥作用 在驱动炎症中的作用。但是，在机械上仍然不清楚如何产生各种细胞因子 这些细胞可以促进心肌炎症和疾病的进展到更严重和致命的结果。 有趣的是，我们的初步工作表明白介素（IL）-3，一种来自菌落刺激因子的细胞因子 （CSF）家族在实验性自身免疫性心肌炎（EAM）的峰值期间驱动心脏炎症。 例如，我们最近发现IL-3缺陷小鼠受到EAM中心脏炎症的保护。 在分析心脏白细胞时，我们发现IL-3是由CD4+ T辅助（Th）细胞专门产生的 EAM的峰，并确定心脏MHC-II+巨噬细胞，单核细胞和单核细胞衍生的树突状 细胞（MODC）在EAM峰值表达IL-3受体（IL-3R），从而将这些IL-3R+细胞识别为 推定的IL-3响应者。这些数据共同提出了一个中心假设，即IL-3是必不可少的 用于驱动T细胞介导的心肌炎的心脏炎症。 在这里，我旨在检查使用两个特征良好的IL-3介导的机制，这些机制驱动炎症 心肌炎的小鼠模型（即EAM和Coxsackievirus B3（CVB3）诱导的心肌炎）。我的具体目标 如下：（i）我将评估IL-3：IL-3R信号传导如何调节白细胞动力学在心肌炎中 心脏和外围。 （ii）我将定义IL-3产生T细胞的谱系起源和特征 心肌炎。 （iii）最后，我还将评估靶向IL-3/IL-3R信号心肌炎的功效 炎症和疾病结果。利用遗传基因敲除小鼠，各种体内和体外分析，流动 我旨在确定如何确定细胞仪和细胞分选，分子生物学，组织学和成像技术 IL-3：IL-3R信号传导塑造白细胞功能，识别子集T细胞T细胞，这些细胞是IL-3介导的心脏的驱动因素 炎症和发现与改善心肌相关的生物学靶标 炎症，阻碍疾病进展和预防猝死。