Classical Dendritic Cells Contribute to Hypoxia-Induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. While there is compelling evidence that bone marrow-derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and that they contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild-type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2+ MHCII+ CCR2+ and FolR2+ MHCII+ CCR2-). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof-of-concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs in the pathophysiology of PH. Overall design: ZBTB46 DTR chimera mice were treated either with a vehicle (PBS) or diphtheria toxin (N=3 in each group). The transcription factor ZBTB46 is controlled by a diphtheria toxin promoter (DTR). Therefore, we deplete classical dendritic cells upon injection of diphtheria toxin. Mice from both groups were exposed to 7 days of hypoxia (FiO2 10%) 1 day before lung collection. RNA was extracted from whole lungs. Our goal was to identify processes related to protection from hypoxia-induced pulmonary hypertension observed in these mice.