Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway

• Published in: Experimental & molecular medicine 2020, 52(0), , pp.1-8
• Main Authors: Ng, Benjamin, Cook, Stuart A., Schafer, Sebastian
• Format: Article
• Language: English
• Subjects: 631/250/127/1213; 631/80/86/2368; Animals; Antibodies; Autocrine signalling; Biomarkers; Biomedical and Life Sciences; Biomedicine; Bleomycin; Cell activation; Cellular Senescence - genetics; Cellular Senescence - immunology; Clinical trials; Connective tissues; COVID-19; Cytokines; Cytokines - metabolism; Disease Susceptibility; Epithelial cells; Epithelium; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Humans; Immune response; Immunotherapy; Inflammation; Inflammation - diagnosis; Inflammation - etiology; Inflammation - metabolism; Inflammation Mediators - metabolism; Innate immunity; Interleukin 11; Interleukin-11 - metabolism; Lung diseases; MAP Kinase Signaling System; Medical Biochemistry; Mesenchyme; Molecular Medicine; Parenchyma; Pulmonary fibrosis; Respiratory Function Tests; Respiratory Tract Diseases - diagnosis; Respiratory Tract Diseases - etiology; Respiratory Tract Diseases - metabolism; Review; Review Article; Risk factors; Signal Transduction; Stem Cells; Stroma; Therapeutic targets; Transforming growth factor-b; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-020-00531-5

Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction. Lung disease: suppressing immune protein could reduce fibrosis An immune protein that contributes to fibrosis, inflammation, and cellular dysfunction in the airways should be a target of therapies for severe lung diseases. Previously thought of as protective, the cytokine interleukin-11 (IL-11) evolved as part of the body’s immune system, and is highly expressed in the parenchyma and stroma of the diseased lung. Sebastian Schäfer at National Heart Centre Singapore and co-workers review recent research evidence indicating that IL-11 signaling is centrally important in pathological processes including the dysfunction of epithelial cells, inflammation of connective tissue, and the activation of cells that induce fibrotic scarring. Antibody therapies targeting IL-11 can reduce pulmonary fibrosis and inflammation in mice. Pharmacological companies may soon begin clinical trials of anti-IL-11 therapies on patients with idiopathic pulmonary fibrosis, a severe lung disease sharing several risk factors with COVID-19.