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Macrophage Circadian Clock Disruption and Inflammation in Heart Failure

心力衰竭中的巨噬细胞生物钟破坏和炎症

基本信息

批准号：
9764124
负责人：
Sumanth D Prabhu
金额：
$ 58.27万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764124
关键词：
ARNTL gene Ablation Agonist Back Behavior Biology Blood Bone Marrow Cardiac Cardiovascular system Cell physiology Cells Characteristics Chronic Clinical Complex Congestive Heart Failure Coronary Data Development Disease Progression E4BP4 Exhibits Fibrosis Functional disorder Genes Genetic Genetic Transcription Heart Heart failure Hematopoietic Human Immune Immune Cell Activation Immunomodulators Infiltration Inflammation Inflammatory Injury Knock-out Knockout Mice Knowledge Left Left Ventricular Remodeling Leukocytes Ligation Link Measures Modeling Molecular Molecular Target Monocytosis Mus Myelogenous Myocardial Infarction Myocardial Ischemia Pathogenesis Pathologic Periodicity Phagocytosis Pharmacology Phenotype Physiological Pilot Projects Play Population Progressive Disease Regulation Role Spleen Testing Therapeutic Tissues Transcription Repressor/Corepressor Translating Up-Regulation Variant Ventricular Wild Type Mouse base beta-Chemokines chemokine chemokine receptor circadian circadian pacemaker clinical practice clinical translation cytokine gamma-Chemokines genetic predictors immune activation immunomodulatory therapies immunoregulation in vivo innovation macrophage molecular clock monocyte novel novel strategies outcome forecast recruit response small molecule therapeutic target transcription factor translational approach

项目摘要

Monocytes and macrophages fundamentally originating from the bone marrow and spleen - pro-inflammatory Ly6Chi monocytes in mice (CD14hi cells in humans) and C-C chemokine receptor 2 (CCR2)+ monocyte-derived macrophages (MDMs) - contribute importantly to tissue injury and left ventricular (LV) remodeling in chronic heart failure (HF), suggesting that these cells may represent therapeutic targets for immunomodulation. Importantly, monocytes and MDMs exhibit circadian variation in multiple functional parameters, in large part due to a robust cell-autonomous molecular clock, which is regulated by the CLOCK/BMAL1 transcriptional complex and subject to an autoregulatory loop involving Rev-erba. Notably, whether the intrinsic circadian clock in monocytes and MDMs is disrupted in HF and its mechanistic link to inflammation and disease progression is entirely unknown. Our pilot studies suggest that monocyte and MDM clock disruption is characteristic of HF, and that monocyte/macrophage Bmal1 (and subsequent Rev-erba/b) loss is associated with upregulation of the immune activator E4bp4, and aggravation of LV remodeling. Based on these data, we hypothesize that the monocyte/MDM clock is dysfunctional in HF, leading to pathological inflammation and cardiac remodeling in a REV-ERBa-linked and E4BP4-dependent manner, and that clock correction is a key molecular target for immunomodulation. Three Aims will test this hypothesis. In Aim 1, we will define alterations in the monocyte circadian clock in HF using a murine coronary ligation model, and test whether monocyte/macrophage clock disruption in myeloid-specific Bmal1 knockout (MBK) mice exacerbates inflammation, innate immune expansion, and LV remodeling during HF. We will also measure inflammatory and clock genes in CD14hi monocytes from humans with HF. In Aim 2, we will delineate the role of monocyte-localized E4bp4, a clock-controlled inflammatory transcription factor and direct target of Rev-erba, in HF by assessing inflammation and LV remodeling after coronary ligation in myeloid-specific E4bp4 knockout (MEK) mice. We will also evaluate whether monocyte E4BP4 suppression rescues the aggravated LV remodeling observed with monocyte/macrophage clock disruption by inducing HF in myeloid-specific Bmal1/E4bp4 double knockout mice. In Aim 3, we will mechanistically establish the potential of targeting the circadian clock as a therapeutic approach in HF, by testing whether treatment with SR9009, a synthetic REV-ERBa/b agonist, favorably modulates monocytes and MDMs and ameliorates or reverses LV remodeling in wild-type mice with established HF, and then in MEK HF mice to determine whether the effects of SR9009 require monocyte/macrophage E4bp4. We will also evaluate the ex vivo activation responses of human HF CD14hi monocytes to the agonist. These studies will further our understanding of how changes in the macrophage circadian clock modulate both inflammation and disease progression in HF, and test novel approaches to immunomodulation using genetic and pharmacological strategies to correct the pathological changes induced by clock disruption.

单核细胞和巨噬细胞基本上源自骨髓和脾脏 - 促炎细胞小鼠 Ly6Chi 单核细胞（人类 CD14hi 细胞）和 C-C 趋化因子受体 2 (CCR2)+ 单核细胞来源巨噬细胞 (MDM) - 对慢性心脏病的组织损伤和左心室 (LV) 重塑有重要作用失败（HF），表明这些细胞可能代表免疫调节的治疗靶点。重要的是，单核细胞和 MDM 在多个功能参数中表现出昼夜节律变化，这在很大程度上是由于强大的细胞自主分子时钟，由 CLOCK/BMAL1 转录复合物和主题调节涉及 Rev-erba 的自动调节循环。值得注意的是，单核细胞的内在生物钟和 MDM 在心力衰竭中被破坏，其与炎症和疾病进展的机制联系完全未知。我们的初步研究表明，单核细胞和 MDM 时钟扰乱是 HF 的特征，并且单核细胞/巨噬细胞 Bmal1（以及随后的 Rev-erba/b）丢失与免疫上调相关激活剂 E4bp4，并加剧 LV 重塑。根据这些数据，我们假设心力衰竭时单核细胞/MDM 时钟功能失调，导致病理性炎症和心脏重塑 REV-ERBa 连接和 E4BP4 依赖方式，并且时钟校正是关键分子目标免疫调节。三个目标将检验这一假设。在目标 1 中，我们将定义单核细胞的改变使用小鼠冠状动脉结扎模型研究心力衰竭的生物钟，并测试单核细胞/巨噬细胞时钟是否骨髓特异性 Bmal1 敲除 (MBK) 小鼠的破坏会加剧炎症、先天免疫扩张、以及 HF 期间的 LV 重塑。我们还将测量 CD14hi 单核细胞中的炎症和时钟基因患有心力衰竭的人。在目标 2 中，我们将描述单核细胞定位的 E4bp4 的作用，这是一种时钟控制的炎症转录因子和 Rev-erba 的直接靶点，通过评估炎症和左心室在心力衰竭中的作用骨髓特异性 E4bp4 敲除 (MEK) 小鼠冠状动脉结扎后的重塑。我们还将评估是否单核细胞 E4BP4 抑制可挽救单核细胞/巨噬细胞观察到的加剧的左室重塑通过在骨髓特异性 Bmal1/E4bp4 双敲除小鼠中诱导 HF 来破坏时钟。在目标 3 中，我们将通过测试，机械地确定以生物钟为目标作为心力衰竭治疗方法的潜力使用 SR9009（一种合成 REV-ERBa/b 激动剂）治疗是否可以有利地调节单核细胞和 MDM 并改善或逆转患有心力衰竭的野生型小鼠的左室重塑，然后在 MEK 心力衰竭小鼠中改善或逆转左心室重塑确定 SR9009 的作用是否需要单核细胞/巨噬细胞 E4bp4。我们也会评估前任人 HF CD14hi 单核细胞对激动剂的体内激活反应。这些研究将进一步推动我们了解巨噬细胞生物钟的变化如何调节炎症和疾病心力衰竭的进展，并使用遗传和药理学测试免疫调节的新方法纠正由时钟中断引起的病理变化的策略。