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，尚未成功地转化为临床实践的慢性心力衰竭（HF）的免疫调节疗法。最近，我们描述了缺血性HF中迄今未批准的不良心铂轴，促炎性脾细胞归因于失败的心脏诱发组织损伤。这个令人兴奋的发现支持免疫调节的新方法 - 一种直接针对特定白细胞和/或脾细胞种群的方法。我们最近的研究表明，脾脏边缘区（MZ）巨噬细胞在缺血性HF中炎症和LV重塑的起源中起重要作用。由两种细胞类型组成 - CD-169+边缘金属噬巨噬细胞（MMMS）和MIGN-R1+ MARCO+ MZ巨噬细胞（MZMS） - 这些专业的巨噬细胞是促炎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HF的慢性炎症，LV重塑和疾病进展至关重要，从而是免疫调节的关键细胞靶标。我们概述了三个旨在检验这一假设的目的。在AIM 1中，我们将使用鼠冠状连接模型和假手术对照来描述慢性HF中MMMS/MZM的运输。 MZ巨噬细胞及其激活曲线将通过流式细胞仪和纵隔淋巴结在连接后的几个时间点通过流式细胞仪和纵隔淋巴结进行测量，无论是在缺乏脾切除术和存在时，都与LV重塑和炎症相关。 MZ巨噬细胞的浸润动力学将通过将CD45.2的异位移植物的异位移植到具有或没有脾切除术进行的CD45.1 HF小鼠中，并测量供体和受体衍生的MZM和MMM MMM损失与在移植的心中积累的供体和受体的时间动力学。在目标2中，我们将通过选择性（和可逆地）使用脂质体（clodronica）和遗传（CD169-DTRTG小鼠）接近损失的损失，并在HF期间选择性（和可逆地）在HF期间有选择地（和可逆地）耗尽MMM和MZM，从而定义MZ巨噬细胞在炎症和LV重塑的发病中的作用，然后将损失的损失效果评估为损失，并在损失上进行了损失，并具有损失的损失，并具有损失的效果。重塑。在AIM 3中，我们将确定MZ巨噬细胞是否是缺血性HF中有害心铂轴的必要驱动因素。带有HF的CD169-DTR TG小鼠的CD45.2单核脾细胞将通过有或没有先前的MZ巨噬细胞消融。我们还将将CD45.1 HF脾细胞转移到CD45.2 CD169-DTR TG小鼠中，然后在受体中长期耗尽MZ巨噬细胞。脾细胞转移对LV/脾重塑，炎症和免疫细胞谱的影响将在受体小鼠中测量。同时，我们将评估来自HF和假小鼠的MZ巨噬细胞在体外激活幼稚的脾淋巴细胞的能力。这些重要的研究将进一步理解慢性缺血性HF炎症和免疫激活的细胞基础，并就最近发现的促炎和组织不良的心肺轴的基本基础提供了创新的观点。