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

摘要 低血压性肺动脉高压（HPH）的特征是右心室压力升高， 血管重塑和阻力，而且往往是致命的。免疫失调是 疾病的病理生理学，这是由周围炎性细胞数量增加所支持的。 重塑的血管以及患者血浆中存在的高水平的炎性细胞因子 不同的PH值。树突状细胞（DC）是专职抗原呈递细胞，其扫描并 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：cDC 1（CD 11b-/CD 103+）和cDC 2（CD 11b+）。 活化的树突状细胞通过分泌趋化因子和细胞因子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cDC驱动 幼稚T细胞极化成不同的效应表型，最重要的是CD 4 +/Th 17细胞， 与实验性HPH有关因此，有大量证据表明， 树突状细胞是PH相关免疫反应的协调者，包括它们的增强存在 在不同PH病因的重塑血管周围;然而，很少有研究 这些细胞可能参与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cDC 2，是肺内炎症的触发因素。 缺氧诱导HPH;单核细胞/巨噬细胞募集和Th 17极化可能依赖于 在CDC。本项目的总体目标是确定经典树突状细胞的机制作用 亚群cDC 2，在驱动促重塑血小板反应蛋白-1表达单核细胞的募集中， 肺，以及引导T细胞反应，从而导致缺氧肺血管重塑 高血压（HPH）。该项目将在肺血管疾病方面具有高度创新性， 作为继续探索这一丰富的调查研究领域的基础，这对我来说至关重要。 过渡到独立调查员。

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.