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: 10350418
• 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/10350418
• 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; Investigation; Knockout Mice; Lead; Life Expectancy; Link; Location; Lung; Molecular; Mus; Natural Immunity; Obstructive Sleep Apnea; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Persons; Phenotype; Plasma; Population; Pulmonary Hypertension; Pulmonary Inflammation; Pulmonary Vascular Resistance; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Right ventricular structure; Role; Scanning; Sense Organs; Shapes; Site; Stimulus; 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; macrophage; 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 低氧肺动脉高压（HPH）的特征是右心室压力升高，增加 血管重塑和抗性，通常是致命的。免疫失调的基础 该疾病的病理生理学，这是由周围炎症细胞数量升高的支持 重塑血管以及患者血浆中存在的高水平炎性细胞因子 来自不同的pH组。树突状细胞（DC）是扫描和 感知他们的组织微环境，协调先天和适应性免疫回报。古典 树突状细胞（CDC）分为两个不同的子集：CDC1（CD11B-/CD103+）和CDC2（CD11B+）。 激活的DC通过分泌趋化因子和细胞因子来改变其即时组织微环境 吸引其他炎症细胞，包括单核细胞/巨噬细胞。此外，激活的CDC驱动器 天真的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相关免疫反应的编排者，包括它们的增强存在 围绕pH的不同病因重塑视频；但是，很少有人解决 这些细胞可以参与pH的致​​病机制。我们的初步数据表明 骨髓衍生的CDC，特别是在低氧pH肺中增加的CDC2，是触发器的触发因素 缺氧引起的HPH；单核细胞/巨噬细胞募集和TH17极化可能取决于 在CDC上。该项目的总体目标是确定经典树突细胞的机械作用 子集cdc2，在推动促启动造型血小板素-1-表达单核细胞的招募时 肺以及指导T细胞反应，引起低氧肺的血管重塑 高血压（HPH）。该项目将在肺血管疾病中具有很高的创新性，并将服务 作为继续探索这个丰富的调查研究领域的基础，这对我的 过渡到独立研究者。