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.

心肌炎是一种异质性心肌炎性疾病， 炎症病理学。它可以表现为从轻度亚临床疾病到严重后果，包括 心源性休克，危及生命的心律失常，甚至猝死。虽然许多患者从 心肌炎相关的急性疾病，心肌炎症的长期后遗症涉及 炎症性扩张型心肌病和慢性心力衰竭的发展， 选择非常有限。鉴于心肌炎是一种高度多态性的疾病， 治疗指南不存在，重要的是要确定共同的潜在机制， 心肌炎症，以便更好地预防与心肌炎相关的发病率和死亡率。 迄今为止，关于心肌炎发病机制的大多数信息是从动物身上收集的， 模拟自身免疫性和病毒性心肌炎的模型。在这些模型中，CD 4 + T细胞发挥主要作用。 驱动炎症的作用。然而，在机制上仍然不清楚细胞因子是如何产生的。 这些细胞可以促进心肌炎症和疾病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，白细胞介素（IL）-3，从集落刺激因子的细胞因子， (CSF)在实验性自身免疫性心肌炎（EAM）的高峰期， 例如，我们最近发现IL-3缺陷小鼠在EAM中免受心脏炎症的影响。 在分析心脏白细胞后，我们发现IL-3是由CD 4 + T辅助细胞（TH）特异性产生的， EAM的峰值，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 细胞（moDC）在EAM的峰值表达IL-3受体（IL-3R），因此将这些IL-3R+细胞鉴定为 假定的IL-3应答者。总之，这些数据使我们提出了中心假设，即IL-3是必不可少的 在心肌炎中驱动T细胞介导的心脏炎症。 在这里，我的目的是研究IL-3介导的机制，驱动炎症使用两个良好的表征， 小鼠心肌炎模型（即EAM和柯萨奇病毒B3（CVB 3）诱导的心肌炎）。我的具体目标 如下：（I）我将评估IL-3：IL-3R信号传导如何调节心肌炎中白细胞动力学， 心脏和外周。(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信号传导心肌炎的疗效。 炎症和疾病结果。利用基因敲除小鼠，各种体内和体外分析， 细胞计数和细胞分选，分子生物学，组织学和成像技术，我的目标是确定如何 IL-3：IL-3R信号传导塑造白细胞功能，识别T细胞亚群，它们是IL-3介导的心脏 炎症，并揭示与改善心肌炎治疗相关的生物靶点， 炎症，阻碍疾病进展，防止猝死。