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

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.