Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension.

Abstract

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 MyD88(fl/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 MyD88(fl/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.

• Authors: Aurélien Parpaleix, Valérie Amsellem, Amal Houssaini, Shariq Abid, Marielle Breau, Elisabeth Marcos, Daigo Sawaki, Marion Delcroix, Rozenn Quarck, Aurélie Maillard, Isabelle Couillin, Bernhard Ryffel, Serge Adnot
• Journal: The European respiratory journal (Eur Respir J) Vol. 48 Issue 2 Pg. 470-83 (08 2016) ISSN: 1399-3003 [Electronic] England
• PMID: 27418552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2016.

Chemical References

• Culture Media, Conditioned
• IL1R1 protein, human
• IL1R1 protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• MYD88 protein, human
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• Receptors, Interleukin-1 Type I
• Monocrotaline

Topics

• Animals
• Cell Differentiation
• Cell Proliferation
• Culture Media, Conditioned (chemistry)
• Gene Deletion
• Humans
• Hypertension, Pulmonary (metabolism)
• Inflammation
• Interleukin 1 Receptor Antagonist Protein (chemistry)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Monocrotaline (chemistry)
• Myeloid Differentiation Factor 88 (metabolism)
• Myocytes, Smooth Muscle (metabolism)
• NF-kappa B (metabolism)
• Rats
• Rats, Wistar
• Receptors, Interleukin-1 Type I (metabolism)
• Signal Transduction