RT Journal Article
SR Electronic
T1 Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 470
OP 483
DO 10.1183/13993003.01448-2015
VO 48
IS 2
A1 Aurélien Parpaleix
A1 Valérie Amsellem
A1 Amal Houssaini
A1 Shariq Abid
A1 Marielle Breau
A1 Elisabeth Marcos
A1 Daigo Sawaki
A1 Marion Delcroix
A1 Rozenn Quarck
A1 Aurélie Maillard
A1 Isabelle Couillin
A1 Bernhard Ryffel
A1 Serge Adnot
YR 2016
UL http://erj.ersjournals.com/content/48/2/470.abstract
AB Pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation are key components of pulmonary arterial hypertension (PAH). Interleukin (IL)-1β binds to IL-1 receptor (R)1, thereby recruiting the molecular adaptor myeloid differentiation primary response protein 88 (MyD88) (involved in IL-1R1 and Toll-like receptor signal transduction) and inducing IL-1, IL-6 and tumour necrosis factor-α synthesis through nuclear factor-κB activation.We investigated the IL-1R1/MyD88 pathway in the pathogenesis of pulmonary hypertension.Marked IL-1R1 and MyD88 expression with predominant PA-SMC immunostaining was found in lungs from patients with idiopathic PAH, mice with hypoxia-induced pulmonary hypertension and SM22-5-HTT+ mice. Elevations in lung IL-1β, IL-1R1, MyD88 and IL-6 preceded pulmonary hypertension in hypoxic mice. IL-1R1−/−, MyD88−/− and control mice given the IL-1R1 antagonist anakinra were protected similarly against hypoxic pulmonary hypertension and perivascular macrophage recruitment. Anakinra reversed pulmonary hypertension partially in SM22-5-HTT+ mice and markedly in monocrotaline-treated rats. IL-1β-mediated stimulation of mouse PA-SMC growth was abolished by anakinra and absent in IL-1R1−/− and MyD88−/− mice. Gene deletion confined to the myeloid lineage (M.lys-Cre MyD88fl/fl mice) decreased pulmonary hypertension severity versus controls, suggesting IL-1β-mediated effects on PA-SMCs and macrophages. The growth-promoting effect of media conditioned by M1 or M2 macrophages from M.lys-Cre MyD88fl/fl mice was attenuated.Pulmonary vessel remodelling and inflammation during pulmonary hypertension require IL-1R1/MyD88 signalling. Targeting the IL-1β/IL-1R1 pathway may hold promise for treating human PAH.The IL-1R1/MyD88 pathway is a treatment target for pulmonary arterial hypertension http://ow.ly/1Fpe3008RLs