Splenic Marginal Zone Macrophages in Chronic Ischemic Heart Failure

慢性缺血性心力衰竭中的脾边缘区巨噬细胞

基本信息

批准号：
9211359
负责人：
Sumanth D Prabhu
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-10 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211359
关键词：
Ablation Adoptive Transfer Antibodies Antigen-Presenting Cells Antigens Apoptosis Arthritis Atherosclerosis Blood C57BL/6 Mouse Cardiac Cardiac Myocytes Cell Separation Cells Chronic Clinical Clinical Trials Congestive Heart Failure Coronary Data Dendritic Cells Development Dichloromethylene Diphosphonate Diphtheria Toxin Disease Disease Progression Dose Encephalitis Fibrosis Flow Cytometry Genes Genetic Glomerulonephritis Heart Heart Transplantation Heart failure Heterotopic Transplantation Home environment Homing Human Hypertrophy Immune Immune Tolerance Immunohistochemistry In Vitro Infarction Infiltration Inflammation Inflammatory Injury Kinetics Left Left Ventricular Dysfunction Left Ventricular Remodeling Leukocytes Ligation Liposomes Macrophage Activation Measures Mediastinal lymph node group Mediator of activation protein Modeling Mononuclear Mus Myocardial Ischemia Myocardium Natural Immunity PTPRC gene Pathogenesis Pathologic Patients Phagocytes Play Population Progressive Disease Role Signal Transduction Spleen Splenectomy Splenocyte T-Lymphocyte TNF gene TNFRSF5 gene Testing Therapeutic Time Tissues Transgenic Mice Translating Ventricular Work adaptive immunity base cell type cellular targeting clinical practice cytokine diphtheria toxin receptor immune activation immunoregulation in vitro Assay innovation loss of function macrophage monocyte mortality mouse dectin-2 neovascularization novel novel strategies outcome forecast public health relevance receptor response therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): To date, no immunomodulatory therapies for chronic heart failure (HF) have been successfully translated to clinical practice. Recently, we described a heretofore unappreciated adverse cardiosplenic axis in ischemic HF, with pro-inflammatory splenocytes homing to the failing heart to induce tissue injury. This exciting discovery supports a new approach to immunomodulation - one that directly targets specific leukocyte and/or splenocyte populations. Our recent studies suggest an important role for splenic marginal zone (MZ) macrophages in the genesis of inflammation and LV remodeling in ischemic HF. Comprised of two cell types - CD-169+ marginal metallophilic macrophages (MMMs) and SIGN-R1+MARCO+ MZ macrophages (MZMs) - these specialized macrophages are pro-inflammatory and broad immune activators. Based on our preliminary data, we hypothesize that MZ macrophage activation is essential for chronic inflammation, LV remodeling, and disease progression in HF, and thereby are key cellular targets for immunomodulation. We outline three Aims to test this hypothesis. In Aim 1, we will delineate trafficking of MMMs/MZMs in chronic HF using a murine coronary ligation model and sham-operated controls. MZ macrophages and their activation profiles will be measured in heart, blood, spleen, and mediastinal lymph nodes by flow cytometry and immunohistochemistry at several time points after ligation, both in the absence and presence of splenectomy, and correlated with LV remodeling and inflammation. The infiltration dynamics of MZ macrophages will be determined by heterotopic transplantation of CD45.2 failing hearts into CD45.1 HF mice with or without splenectomy, and measuring the temporal kinetics of donor- and recipient-derived MZM and MMM loss vs. accumulation in the transplanted heart. In Aim 2, we will define the role of MZ macrophages in the pathogenesis of inflammation and LV remodeling by selectively (and reversibly) depleting MMMs and MZMs during HF using both liposomal (clodronate) and genetic (CD169-DTR Tg mice) approaches, and then evaluating the effects of loss-of-function on inflammation, immune cell profiles, and LV and splenic remodeling. In Aim 3, we will establish whether MZ macrophages are essential drivers of the detrimental cardiosplenic axis in ischemic HF. CD45.2 mononuclear splenocytes from CD169-DTR Tg mice with HF will be adoptively transferred into CD45.1 naive mice, with or without prior MZ macrophage ablation. We will also transfer CD45.1 HF splenocytes into CD45.2 CD169-DTR Tg mice and then chronically deplete MZ macrophages in recipients. The effects of splenocyte transfer on LV/splenic remodeling, inflammation, and immune cell profiles will be measured in recipient mice. In parallel, we will evaluate the ability of MZ macrophages from HF and sham mice to activate naive splenic T- lymphocytes in vitro. These important studies will further our understanding of the cellular basis for inflammatory and immune activation in chronic ischemic HF, and provide innovative perspectives as to the fundamental underpinnings of the recently discovered pro-inflammatory and tissue-injurious cardiosplenic axis.

描述（由申请人提供）：迄今为止，还没有针对慢性心力衰竭（HF）的免疫调节疗法成功转化为临床实践。最近，我们描述了缺血性心力衰竭中迄今为止未被认识到的不良心脾轴，促炎性脾细胞归巢至衰竭的心脏以诱导组织损伤。这一令人兴奋的发现支持了免疫调节的新方法 - 一种直接针对特定白细胞和/或脾细胞群的方法。我们最近的研究表明脾边缘区 (MZ) 巨噬细胞在缺血性心力衰竭炎症和左心室重塑的发生中发挥重要作用。由两种细胞类型组成 - CD-169+ 边缘嗜金属巨噬细胞 (MMM) 和 SIGN-R1+MARCO+ MZ 巨噬细胞 (MZM) - 这些特殊的巨噬细胞是促炎性和广泛的免疫激活剂。根据我们的初步数据，我们假设 MZ 巨噬细胞激活对于慢性炎症、左心室重塑和心力衰竭疾病进展至关重要，因此是免疫调节的关键细胞靶点。我们概述了检验这一假设的三个目标。在目标 1 中，我们将使用小鼠冠状动脉结扎模型和假手术对照来描述慢性心力衰竭中 MMM/MZM 的贩运。将在结扎后的几个时间点（无论是否存在脾切除术）通过流式细胞术和免疫组织化学在心脏、血液、脾脏和纵隔淋巴结中测量 MZ 巨噬细胞及其激活谱，并与左室重塑和炎症相关。 MZ 巨噬细胞的浸润动力学将通过将 CD45.2 衰竭心脏异位移植到带或不带脾切除的 CD45.1 HF 小鼠中来确定，并测量供体和受体来源的 MZM 和 MMM 损失与累积的时间动力学。移植的心脏。在目标 2 中，我们将通过使用脂质体（氯膦酸盐）和遗传（CD169-DTR Tg 小鼠）方法在心力衰竭期间选择性（并可逆地）消耗 MMM 和 MZM 来定义 MZ 巨噬细胞在炎症和 LV 重塑发病机制中的作用，以及然后评估功能丧失对炎症、免疫细胞特征以及左室和脾重塑的影响。在目标 3 中，我们将确定 MZ 巨噬细胞是否是缺血性心力衰竭中有害心脾轴的重要驱动因素。来自患有 HF 的 CD169-DTR Tg 小鼠的 CD45.2 单核脾细胞将被过继转移到 CD45.1 幼稚小鼠中，无论有或没有事先 MZ 巨噬细胞消融。我们还将 CD45.1 HF 脾细胞转移到 CD45.2 CD169-DTR Tg 小鼠中，然后长期消耗受体中的 MZ 巨噬细胞。将在受体小鼠中测量脾细胞转移对左心室/脾重塑、炎症和免疫细胞谱的影响。同时，我们将评估 HF 小鼠和假小鼠的 MZ 巨噬细胞在体外激活初始脾 T 淋巴细胞的能力。这些重要的研究将进一步加深我们对慢性缺血性心力衰竭炎症和免疫激活的细胞基础的理解，并为最近发现的促炎症和组织损伤心脾轴的基本基础提供创新视角。