Toll-like receptor 3 is a therapeutic target for pulmonary hypertension

Journal article

Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. Toll-like receptor 3 (TLR3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection. Objective: The goal was to study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces Pulmonary Hypertension in preclinical models. Methods: Lung tissue and endothelial cells from PAH patients were investigated by polymerase chain reaction, immunofluorescence and apoptosis assays. TLR3-/- and TLR3+/+ mice were exposed to chronic hypoxia and SU5416. Chronic hypoxia or chronic hypoxia/SU5416 rats were treated with the TLR3 agonist polyinosinic:polycytidylic acid [Poly(I:C)]. Measurements and Main Results: TLR3 expression was reduced in PAH patient lung tissue and endothelial cells, and TLR3-/- mice exhibited more severe Pulmonary Hypertension following exposure to chronic hypoxia/SU5416. TLR3 knockdown promoted double-stranded RNA signaling via other intracellular RNA receptors in endothelial cells and this was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(I:C) increased TLR3 expression via interleukin-10 in rat endothelial cells. In vivo, high dose Poly(I:C) reduced Pulmonary Hypertension in both rat models in proof-of-principle experiments. In addition, Poly(I:C) also reduced right ventricular failure in established Pulmonary Hypertension. Conclusions: Our work identifies a novel role for TLR3 in PAH based on the findings that reduced expression of TLR3 contributes to endothelial apoptosis and pulmonary vascular remodeling.

Authors: Farkas, D; Thompson, AAR; Bhagwani, AR; Hultman, S; Ji, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Thoracic Society
• Journal: American Journal of Respiratory and Critical Care Medicine More from this journal
• Volume: 199
• Issue: 2
• Pages: 199–210
• Publication date: 2018-09-13
• Acceptance date: 2018-07-03
• DOI: 10.1164/rccm.201707-1370OC
• EISSN: 1535-4970
• ISSN: 1073-449X
• Keywords: pulmonary hypertension; apoptosis; toll-like receptor 3; endothelial cell; double stranded RNA