Farkas, D., Thompson, A.A.R. orcid.org/0000-0002-0717-4551, Bhagwani, A.R. et al. (14 more authors) (2018) Toll-like receptor 3 is a therapeutic target for pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X
Abstract
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.
Metadata
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Copyright, Publisher and Additional Information: | © 2018 The American Thoracic Society. This is an author produced version of a paper subsequently published in American Journal of Respiratory and Critical Care Medicine. Uploaded in accordance with the publisher's self-archiving policy. | ||||||
Keywords: | Pulmonary Hypertension; apoptosis; double stranded RNA; endothelial cell; toll-like receptor 3 | ||||||
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Institution: | The University of Sheffield | ||||||
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals | ||||||
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Depositing User: | Symplectic Sheffield | ||||||
Date Deposited: | 19 Sep 2018 11:24 | ||||||
Last Modified: | 13 Mar 2019 01:38 | ||||||
Published Version: | https://doi.org/10.1164/rccm.201707-1370OC | ||||||
Status: | Published online | ||||||
Publisher: | American Thoracic Society | ||||||
Refereed: | Yes | ||||||
Identification Number: | https://doi.org/10.1164/rccm.201707-1370OC | ||||||
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