TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension

• Published in: Nature communications Vol. 8; no. 1; pp. 15494 - 13
• Main Authors: Kumar, Rahul, Mickael, Claudia, Kassa, Biruk, Gebreab, Liya, Robinson, Jeffrey C., Koyanagi, Daniel E., Sanders, Linda, Barthel, Lea, Meadows, Christina, Fox, Daniel, Irwin, David, Li, Min, McKeon, B. Alexandre, Riddle, Suzette, Dale Brown, R., Morgan, Leslie E., Evans, Christopher M., Hernandez-Saavedra, Daniel, Bandeira, Angela, Maloney, James P., Bull, Todd M., Janssen, William J., Stenmark, Kurt R., Tuder, Rubin M., Graham, Brian B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 38/77; 631/250/256/2516; 64/110; 64/60; 692/699/1785; Animals; Antigens, Ly - metabolism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Bone Marrow Cells - metabolism; Cattle; Humanities and Social Sciences; Humans; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - immunology; Hypertension, Pulmonary - parasitology; Hypoxia - complications; Hypoxia - pathology; Lung - blood supply; Lung - metabolism; Lung - pathology; Mice, Inbred C57BL; Monocytes - metabolism; multidisciplinary; RNA, Messenger - genetics; RNA, Messenger - metabolism; Schistosoma - physiology; Science; Science (multidisciplinary); Signal Transduction; Th2 Cells - immunology; Thrombospondin 1 - blood; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Transforming Growth Factor beta - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15494

Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma -exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases. Thrombospondin-1 (TSP-1) activates latent TGF-β in the extracellular matrix. Here the authors show that inappropriate activation of latent TGF-β in murine, bovine and human lung by monocyte-produced TSP-1 causes pulmonary hypertension, and that interference with the activation process prevents disease development.