Immunoglobulin E Mediates Pulmonary Vascular Remodeling by Upregulating Mast Cell Secretion of VEGFC

Pulmonary vascular remodeling (PVR) is a hallmark pathological change of pulmonary hypertension (PH) and plays a very important role in the formation and development of PH. However, no effective therapy has been developed to date to reverse PVR. The present study evaluated the expression and function of immunoglobulin E (IgE) on experimental PH models. Single-cell RNA sequencing on lung tissues from mice subjected to hypoxia-induced PH revealed the existence of active B cells in the lung. A significant increase in IgE expression was observed in the lung tissues of the experimental PH model and PAH patients. Treatment with IgE neutralizing antibodies attenuated hypoxia-induced PH and pulmonary vascular remodeling in mice. VEGFC derived from IgE-stimulated mast cells promoted the proliferation and migration of pulmonary arterial endothelial cells (PAECs) as well as endothelial to mesenchymal transition, and aggravated hypoxia-induced PH in a mast cell-reconstitution model. IgE levels are elevated in PH and promote pulmonary vascular remodeling by VEGFC derived from activated mast cells. Funding Information: This work was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [grant number: 2018-12M-1-001 toC.W.]; the National Natural Science Foundation of China [grant numbers:81622008, 91739107 to J.W.]; the National Natural Science Foundation of China [grant numbers:82000063 to Y.L.]; Thousand Young Talents Program of China to J.W.; the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [grant number:2018JB31001 to C.W.] and State Key Laboratory Special Fund [grant number: 2060204]. Declaration of Interests: The authors have declared no conflicts of interest Ethics Approval Statement: All participants provided written informed consent for the use of the lung tissue for research before enrollment (Approval NO.:2017-877). The study was approved bythe Institutional Ethics Committee of Peking Union Medical College, and conducted according to the Declaration of Helsinki principles. All animal experiments were performed following the protocols approved by the Animal Research Committee of Institute of Laboratory Animals, Chinese Academy of Medical Sciences and Peking Union Medical College (ACUC-A01-2018-005).