• Daniela Farkas, ThompsonA A RogerAAR2 Department of Infection, Immunity & Cardiovascular Disease, Faculty of Medicine, Dentistry & Health, University of Sheffield, Sheffield, United Kingdom., Aneel R Bhagwani, Schuyler Hultman, Hyun Ji, Naveen Kotha, Grant Farr, Nadine D Arnold, Adam Braithwaite, Helen Casbolt, Jennifer E Cole, Ian Sabroe, Claudia Monaco, Carlyne D Cool, Elena A Goncharova, Allan Lawrie, and Laszlo Farkas.
• 1 Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
• Am. J. Respir. Crit. Care Med. 2019 Jan 15; 199 (2): 199210199-210.

RationalePulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection.ObjectivesTo study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces pulmonary hypertension in preclinical models.MethodsLung tissue and endothelial cells from patients with PAH 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 ResultsTLR3 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. This was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(I:C) increased TLR3 expression via IL-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.ConclusionsOur 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.

19 keywords...

hide…