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

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 Schafer 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. 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 (TGF beta) 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.