Mechanisms of Treg and IL-35 in Regulating LV Failure-induced Lung Remodeling and Right Heart Hypertrophy

Treg 和 IL-35 调节左室衰竭所致肺重塑和右心肥厚的机制

• 批准号: 10116063
• 负责人: YINGJIE CHEN
• 金额: $ 54.82万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116063
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Apoptosis; Attenuated; B-Lymphocytes; Cardiac; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Congestive Heart Failure; Dendritic cell activation; Development; Disease; Dyspnea; Exhibits; Failure; Fibrosis; Genes; Goals; Heart; Heart Hypertrophy; Heart failure; Human Herpesvirus 4; IL2 gene; IL2RA gene; Immune Tolerance; Immunosuppression; Infiltration; Inflammation; Interleukin-1 beta; Interleukin-2; Interleukins; Left; Left Ventricular Dysfunction; Left ventricular structure; Leukocytes; Liver; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Memory; Monoclonal Antibodies; Mus; Myocardial Infarction; Myocarditis; Patients; Pilot Projects; Play; Process; Production; Pulmonary Hypertension; Regulatory T-Lymphocyte; Right Ventricular Hypertrophy; Role; Secondary to; Solid; Stroke; Structure of parenchyma of lung; T-Cell Activation; T-Lymphocyte; Therapeutic; Time; Tissues; Ventricular; cardiovascular risk factor; cytokine; heart damage; improved; inhibitor/antagonist; innovation; insight; interest; lung injury; neutralizing antibody; novel; stem

PROJECT SUMMARY The central goal of this project is to investigate the mechanisms of T regulatory cells (Tregs) and interleukin 35 (IL-35) in attenuating lung inflammation and remodeling leading to WHO type-2 pulmonary hypertension (PH), and arresting the transitional process from left ventricular (LV) failure to right ventricular (RV) hypertrophy and failure. While most studies in the chronic heart failure (CHF) field focus on left ventricle, we recently demonstrated that LV failure causes profound lung inflammation, fibrosis, and severe type-2 PH. Remarkably, in some cases lung remodeling is so extensive that the lung tissue becomes as solid as liver tissue in CHF animals. We have now obtained solid evidence that Tregs are effective in suppressing LV failure-induced lung inflammation, and type-2 PH in animals with existing LV failure, but the mechanisms remain unknown. IL-35 is a heterodimer composed of IL-12α (p35) and Epstein-Barr virus-induced gene-3 (EBI3) subunits. IL-35 can effectively promote the formation of Tregs and regulatory B cells (Bregs). Therefore, IL-35 may play an important role in attenuating lung inflammation/remodeling, type-2 PH, and the transition from LV failure to RV hypertrophy and failure through both Treg-dependent or Treg-independent mechanisms. Here we will investigate how Tregs and IL-35 affect CHF-induced lung inflammation, and type- 2 PH. Specific Aim-1 will mainly determine the mechanisms of Tregs and IL-35 in suppressing lung inflammation, type-2 PH, and the transition from LV failure to RV failure in mice with existing LV failure. We will perform the following studies: (i) examine the impact of Treg depletion on IL-35 production, T cell and dendritic cell activation, lung inflammation, type-2 PH, and the transition from LV failure to RV hypertrophy and/or failure in mice, (ii) determine why the ratio of Tregs to T effector memory cells is dramatically reduced in lung tissue in CHF animals, and whether this can be explained by alterations in Treg proliferation or apoptosis, and (iii) determine the mechanism of IL-35 in suppressing lung remodeling and type-2 PH in mice with existing LV failure with a focus on Tregs and T cell activation. Specific Aim-2 will determine the crosstalk between Tregs and IL-35, and their corresponding roles in regulating lung inflammation and type-2 PH in mice with existing LV failure. We will perform following studies: (i) Determine if IL-35 is required for the optimal protection by Treg induction in attenuating lung inflammation, type-2 PH, and the transition from LV failure to RV hypertrophy/failure. (ii) determine the role of IL-35-independent Tregs in attenuating lung inflammation, type-2 PH and CHF progression, and (iii) determine whether administration of IL-35 is sufficient to rescue Treg depletion-induced lung inflammation and type-2 PH in mice with existing LV failure. Successful completion of this project will provide exciting and novel insights into cardiovascular protective mechanism(s) of Tregs and IL-35, and demonstrate the therapeutic potential of targeting Tregs and IL-35 to halt or reverse lung inflammation, and the transition from LV failure to RV hypertrophy and/or failure.

项目概要 该项目的中心目标是研究调节性T细胞（Treg）和白细胞介素的作用机制 35 (IL-35) 可减轻导致 WHO 2 型肺动脉高压的肺部炎症和重塑 (PH)，并阻止从左心室 (LV) 衰竭到右心室 (RV) 的过渡过程 肥大和衰竭。虽然慢性心力衰竭 (CHF) 领域的大多数研究都集中在左心室，但我们 最近证明，左心室衰竭会导致严重的肺部炎症、纤维化和严重的 2 型肺PH。 值得注意的是，在某些情况下，肺重塑非常广泛，以至于肺组织变得像肝脏一样坚固 CHF 动物的组织。我们现在已经获得确凿的证据表明Tregs可以有效抑制LV 左室衰竭引起的肺部炎症和 2 型 PH 已存在 LV 衰竭的动物，但其机制 仍然未知。 IL-35 是由 IL-12α (p35) 和 Epstein-Barr 病毒诱导的基因 3 组成的异二聚体 (EBI3) 亚基。 IL-35能有效促进Tregs和调节性B细胞（Bregs）的形成。 因此，IL-35 可能在减轻肺部炎症/重塑、2 型 PH 和 通过 Treg 依赖性或 Treg 独立性从 LV 衰竭转变为 RV 肥大和衰竭 机制。在这里，我们将研究 Tregs 和 IL-35 如何影响 CHF 诱导的肺部炎症，以及类型 - 2 PH。具体的Aim-1将主要决定Tregs和IL-35抑制肺的机制 炎症、2 型 PH 以及现有 LV 衰竭小鼠从 LV 衰竭到 RV 衰竭的转变。我们 将进行以下研究：(i) 检查 Treg 耗竭对 IL-35 产生、T 细胞和 树突状细胞激活、肺部炎症、2 型 PH 以及从 LV 衰竭到 RV 肥大的转变 和/或小鼠的失败，(ii) 确定为什么 Tregs 与 T 效应记忆细胞的比例显着降低 CHF 动物肺组织中的变化，以及这是否可以通过 Treg 增殖的改变或 (iii) 确定 IL-35 抑制小鼠肺重塑和 2 型 PH 的机制 现有 LV 衰竭，重点关注 Tregs 和 T 细胞激活。具体的Aim-2将决定串扰 Tregs 和 IL-35 之间的关系及其在调节小鼠肺部炎症和 2 型 PH 中的相应作用 现有 LV 故障。我们将进行以下研究： (i) 确定 IL-35 是否是最佳效果所必需的 Treg 诱导在减轻肺部炎症、2 型 PH 以及从 LV 衰竭到转变的过程中提供保护 右心室肥大/衰竭。 (ii) 确定不依赖 IL-35 的 Tregs 在减轻肺部炎症中的作用， 2 型 PH 和 CHF 进展，以及 (iii) 确定给予 IL-35 是否足以挽救 Treg 耗竭可诱导左心室衰竭小鼠肺部炎症和 2 型 PH。成功的 该项目的完成将为心血管保护机制提供令人兴奋和新颖的见解 Tregs 和 IL-35，并证明靶向 Tregs 和 IL-35 阻止或逆转的治疗潜力 肺部炎症，以及从左心室衰竭到右心室肥大和/或衰竭的转变。