Novel Role of Classical Dendritic Cells in the pathogenesis of Hypoxia-Induced Pulmonary Hypertension

经典树突状细胞在缺氧性肺动脉高压发病机制中的新作用

• 批准号: 10689660
• 负责人: Claudia Silva Mickael
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689660
• 关键词: Acute; Address; Affect; Altitude; Antigen-Presenting Cells; Area; Automobile Driving; B-Lymphocytes; Blood Vessels; Bone Marrow; CD4 Positive T Lymphocytes; CD80 gene; CD86 gene; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Data; Dendritic Cells; Development; Disease; Environment; Etiology; Exposure to; Fibrosis; Flow Cytometry; Foundations; Functional disorder; Goals; Grant; Human; Hypoxia; ITGAM gene; Immune; Immune response; Immune system; Immunity; Inflammation; Inflammatory; Innate Immune Response; Investigation; Knockout Mice; Life Expectancy; Link; Location; Lung; Macrophage; Molecular; Mus; Natural Immunity; Obstructive Sleep Apnea; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Persons; Phenotype; Plasma; Population; Pulmonary Hypertension; Pulmonary Vascular Resistance; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Right ventricular structure; Role; Scanning; Sense Organs; Shapes; Site; Stimulus; Subcategory; T cell response; T-Lymphocyte; TNFRSF5 gene; Thrombospondin 1; Tissues; Transforming Growth Factor beta; Vascular remodeling; Vascular resistance; adaptive immune response; adaptive immunity; chemokine; cytokine; effector T cell; hypoxia-induced pulmonary hypertension; innovation; interstitial; lung hypoxia; lung vascular inflammation; mast cell; monocyte; novel; pathogen; pressure; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular disorder; pulmonary vascular remodeling; recruit; response; right ventricular failure

ABSTRACT Hypoxic Pulmonary hypertension (HPH) is characterized by elevated right ventricle pressures, increased vascular remodeling and resistance, and it is often fatal. Dysregulated immunity underlies the pathophysiology of the disease, which is supported by the elevated numbers of inflammatory cells around the remodeled vessels, as well as high levels of inflammatory cytokines present in the plasma of patients from different PH groups. Dendritic cells (DCs) are professional-antigen presenting cells that scan and sense their tissue microenvironment, coordinating innate and adaptive immune responses. Classical dendritic cells (cDCs) are divided in two different subsets: cDC1 (CD11b-/CD103+) and cDC2 (CD11b+). Activated DCs modify their immediate tissue microenvironment by secreting chemokines and cytokines that attract other inflammatory cells, including monocytes/ macrophages. Besides, activated cDCs drive polarization of naïve T cells into different effector phenotypes, most importantly CD4+/Th17 cells, which have been linked to experimental HPH. Therefore, there is a substantial body of evidence indicating that dendritic cells are orchestrators of the PH-related immune response, including their augmented presence around remodeled vessels in different etiologies of PH; however, there are few studies that address pathogenic mechanisms in which these cells could participate in PH. Our preliminary data indicate that bone-marrow-derived cDCs, particularly cDC2 that is increased in hypoxic PH lungs, are triggers of hypoxia-induced HPH; that monocyte/ macrophage recruitment and Th17 polarization may be dependent on cDC. The overall goal of this project is to determine the mechanistic role of the classical dendritic cell subset cDC2, in driving the recruitment of pro-remodeling thrombospondin-1- expressing monocytes to the lung, as well as directing T cell responses, which cause vascular remodeling in hypoxic pulmonary hypertension (HPH). This project will be highly innovative in pulmonary vascular diseases and will serve as a foundation to continue exploring this rich investigative research field, which will be essential to my transition to an independent investigator.

抽象的 缺氧性肺动脉高压（HPH）的特点是右心室压力升高， 血管重塑和抵抗力，这往往是致命的。免疫失调是导致 该疾病的病理生理学，周围炎症细胞数量增加支持这一点 血管重塑以及患者血浆中存在高水平的炎症细胞因子 来自不同的 PH 群体。树突状细胞（DC）是专业的抗原呈递细胞，可以扫描和 感知其组织微环境，协调先天性和适应性免疫反应。古典 树突状细胞 (cDC) 分为两个不同的亚群：cDC1 (CD11b-/CD103+) 和 cDC2 (CD11b+)。 活化的 DC 通过分泌趋化因子和细胞因子来改变其直接组织微环境 吸引其他炎症细胞，包括单核细胞/巨噬细胞。此外，激活的cDCs驱动 将初始 T 细胞极化为不同的效应表型，最重要的是 CD4+/Th17 细胞， 已与实验性 HPH 相关。因此，有大量证据表明 树突状细胞是 PH 相关免疫反应的协调者，包括其增强的存在 PH 不同病因下血管重塑周围；然而，很少有研究涉及 这些细胞参与 PH 的致病机制。我们的初步数据表明 骨髓来源的 cDC，特别是在缺氧 PH 肺中增加的 cDC2，是 缺氧引起的 HPH；单核细胞/巨噬细胞的募集和 Th17 极化可能是依赖的 在CDC上。该项目的总体目标是确定经典树突状细胞的机制作用 cDC2 子集，驱动促重构血小板反应蛋白 1 表达单核细胞的募集 肺，以及指导 T 细胞反应，导致缺氧肺血管重塑 高血压（HPH）。该项目在肺血管疾病方面具有高度创新性，将服务于 作为继续探索这个丰富的调查研究领域的基础，这对我的研究至关重要 过渡为独立调查员。