Inhibition of Immunoglobulin E Attenuates Pulmonary Hypertension

Abstract Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by pathological vascular remodeling in the lung. Immunoglobulin E (IgE) is known to participate in aortic vascular remodeling, but whether IgE mediates pulmonary vascular remodeling in PH is unknown. Here, we found serum IgE elevation in PAH patients, hypoxia-induced PH mice and monocrotaline (MCT)-induced PH rats. Combining animal model of PH with single-cell RNA sequencing, we found IgE production in the lung tissues of PH mice. Neutralizing IgE with an anti-IgE antibody was effective in preventing PH development in mice and rat models. The IgE receptor FcεRIα was also upregulated in PH lung tissues and Fcer1a deficiency prevented the development of PH in mice. Single-cell RNA-seq revealed that FcεRIα was mostly expressed in mast cells, and mast cell-specific Fcer1a knockout protected against PH in mice. Further mechanistic experiments revealed that IgE-activated mast cells produced interleukins IL6 and IL13, which subsequently promoted vascular muscularization. Clinically approved IgE antibody Omalizumab alleviated the progression of established PH in rats. Using genetic and pharmacological approaches, we have demonstrated that blocking IgE- FcεRIα signaling may hold potential for the treatment of PAH.