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.

心肌炎是心肌的一种异质性炎症性疾病，由多种疾病组成 炎症病理学。它可以表现为从轻微的亚临床疾病到严重的结果，包括 心源性休克、危及生命的心律失常，甚至猝死。虽然许多患者已康复 与心肌炎相关的急性疾病，心肌炎症的长期后遗症涉及 炎症性扩张型心肌病和慢性心力衰竭的发展，这两种疾病的治疗 选择非常有限。鉴于心肌炎是一种高度多态性的疾病，且临床具有特殊性 其治疗指南尚不存在，重要的是确定驱动的共同潜在机制 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，大多数有关心肌炎发病机制的信息都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，CD4+ T 细胞发挥着主要作用 驱动炎症的作用。然而，目前尚不清楚各种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，导致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)-3，一种来自集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）高峰期间引发心脏炎症。 例如，我们最近发现 IL-3 缺陷小鼠在 EAM 中可以免受心脏炎症的影响。 在对心脏白细胞进行分析后，我们发现 IL-3 是由 CD4+ T 辅助 (TH) 细胞在 EAM 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 峰值处表达 IL-3 受体 (IL-3R)，因此将这些 IL-3R+ 细胞识别为 假定的 IL-3 反应者。总之，这些数据使我们提出了中心假设：IL-3 至关重要 用于驱动心肌炎中 T 细胞介导的心脏炎症。 在这里，我的目标是使用两种充分表征的方法来检查 IL-3 介导的炎症驱动机制 小鼠心肌炎模型（即 EAM 和柯萨奇病毒 B3 (CVB3) 诱导的心肌炎）。我的具体目标 具体如下： (I) 我将评估 IL-3:IL-3R 信号如何调节心肌炎中的白细胞动态 心脏和外围。 (II) 我将定义产生IL-3的T细胞的谱系起源和特征 心肌炎。 （三）最后我还要评价一下针对IL-3/IL-3R信号传导性心肌炎的疗效 炎症和疾病结果。利用基因敲除小鼠，进行各种体内和体外分析、流程 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，识别驱动 IL-3 介导的心脏功能的 T 细胞亚群 炎症，并发现与改善心肌治疗相关的生物靶点 炎症，阻碍疾病进展，并防止猝死。