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

Eur Respir J. 2016 Aug;48(2):470-83. doi: 10.1183/13993003.01448-2015. Epub 2016 Jul 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • 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