Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis.
Benjamin NgJinrui DongGiuseppe Alessandro D'AgostinoSivakumar ViswanathanAnissa Anindya WidjajaWei Wen LimNicole S J KoJessie TanSonia P ChothaniBenjamin HuangChen XieChee Jian PuaAnn-Marie ChackoNuno Guimarães-CamboaSylvia M EvansAdam J ByrneToby M MaherJiurong LiangDianhua JiangPaul W NobleSebastian SchaferStuart Alexander CookPublished in: Science translational medicine (2020)
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 (IL11) is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2+), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 (Il11ra1)-deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11-neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.
Keyphrases
- idiopathic pulmonary fibrosis
- mouse model
- signaling pathway
- interstitial lung disease
- pulmonary fibrosis
- multiple sclerosis
- oxidative stress
- type diabetes
- systemic sclerosis
- transcription factor
- cell proliferation
- machine learning
- epithelial mesenchymal transition
- skeletal muscle
- metabolic syndrome
- wound healing
- big data
- disease activity
- cell migration