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

• 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
• 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

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，我们在缺血性心衰中描述了一个迄今为止未被认识到的不良心脾轴，促炎脾细胞归巢到衰竭的心脏诱导组织损伤。这一令人兴奋的发现支持了