Targeting Interleukin-17 inflammatory Axis in CTEPH

Chronic thromboembolic pulmonary hypertension (CTEPH) is a deadly sequela following acute pulmonary em- bolism (PE). In CTEPH, the acute PE does not resorb but develops into organized “thrombi,” causing pulmo- nary vascular remodeling, leading to progressive right heart failure and death. The gold standard treatment for CTEPH is surgery, but many patients are not surgical candidates due to comorbidities or surgically inaccessi- ble disease. For these patients, there are only limited options that have only been shown to improve short-term symptoms. Thus, developing novel medical therapies for CTEPH is a significant unmet need. Drug develop- ment has been limited by the significant knowledge gap on how different cell types and signaling pathways within chronic thrombus contribute to pulmonary vascular remodeling and pulmonary hypertension (PH). This puts into context our preliminary studies, using single-cell RNA sequencing (scRNAseq) and ex-vivo culturing of patient thrombus-derived cells, we identified upregulated inflammatory and proliferative signaling pathways that may contribute to chronic thrombus development and pulmonary vascular remodeling. We showed that a phenotypically-modulated smooth muscle cell (SMC) population expresses a high level of PAR1, a receptor that promotes SMC proliferation and migration and propagates IL-17-mediated inflammation. Our data also revealed that SMCs, macrophages, and T cells are enriched for IL-17 signaling, which has been implicated in numerous inflammatory diseases and promotes venous and arterial thrombosis, suggesting a role for the PAR1/IL-17 signaling axis in CTEPH pathogenesis. Thus, our central hypothesis is that the PAR1/IL-17 sig- nal axis propagates abnormal chronic thrombus development and pulmonary vascular remodeling in CTEPH, linking inflammation and pulmonary vascular remodeling in this disease. The overall objective of this applica- tion is to determine the contribution of PAR1/IL-17 signals to the development of abnormal cellular phenotypes in chronic thrombus, initiation, and progression of CTEPH using human samples and animal models. Aim 1 will determine if the PAR1/IL-17 signaling synergistically promotes abnormal thrombus-derived mesenchymal cell phenotypes. In Aim 2, we will evaluate the activity of the PAR1 and IL-17 signaling axes in different immune and mesenchymal cells in human CTEPH using flow cytometry and single-cell technologies. In Aim 3, we will determine whether inhibiting the PAR1/IL-17 signaling axis prevents and reverses CTEPH in vivo using a ro- bust small animal model of CTEPH that we have developed. The rationale for these studies is that defining the mechanisms contributing to inflammation and proliferation will aid the development of novel CTEPH medical therapies. The expected outcome of this project will be to determine whether the PAR1/IL-17 signaling axis promotes disease progression in CTEPH and could serve as a disease target. This will lay the groundwork for future studies on novel CTEPH treatments targeting SMC and immune cell activation. These studies will have a significant positive impact as they will aid in developing new CTEPH therapies. Project Number: 1R01HL174909-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Yen-Rei Yu | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $723,084 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-B (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17490901A1