Abstract Background Interleukin-6 (IL-6) is one of the main cytokines that contribute to pulmonary vascular remodeling in idiopathic, heritable, and connective tissue disease-associated PAH (CTD-PAH). Although previous studies, including clinical trial studies, have examined IL-6 receptor blockade in PAH, clinical results have been inconclusive. Unlike the previous studies, our study directly targets IL-6 using species-specific neutralizing antibodies, disrupting IL-6-driven signaling more precisely. Material and Methods. The therapeutic potential of IL-6 blockade using species-specific anti-IL-6 neutralizing antibodies was evaluated in the Sugen/hypoxia-induced PAH mouse model and a monocrotaline (MCT)-induced PAH rat model. Cardiac MRI, hemodynamics, morphometric, and histological measurements were performed. Bulk RNA sequencing was conducted on mouse lungs, and differential gene expression analysis was performed to identify key molecular pathways affected by IL-6 blockade. Additionally, a cohort of healthy and PAH human serum and lung homogenates, and in vitro studies, were carried out on hPAEC derived from healthy donors and PAH patients using human IL-6 monoclonal neutralizing antibody. Results The treatment of the PAH-diseased animals with species-specific anti-IL6 neutralizing antibodies alleviated RV dysfunction and remodeling and led to a significant decrease in both RVSP and mPAP, with reduced RV and lungs. PAH-related markers, including hypertrophy, fibrosis, inflammation, and oxidative stress markers, were significantly reduced in the IL-6 treatment groups compared to diseased models. RNA sequencing transcriptomic analysis showed that FOXP3, a master regulator of regulatory T cells, was among the top downregulated genes in the PAH animal model and human serum samples, while STAT3 expression was elevated, highlighting an inverse regulatory axis. Foxp3 as a biomarker is also inversely correlated with IL-6 level and PAH patients’ outcomes. In PAECs, IL-6 neutralization restored Foxp3 by repressing both Foxp3 DNA methylation and STAT3 interaction at Foxp3 promoter binding, suggesting that blocking IL-6/STAT3 axis and signaling restores FOXP3 and attenuates vascular inflammation and remodeling in PAH. This abstract is funded by: NIH
Hadri et al. (Fri,) studied this question.