Targeting ADAM-17/Notch Signaling Abrogates the Development of Systemic Sclerosis in a Murine Model

Objective. Systemic sclerosis (SSc) is characterized by the fibrosis of various organs, vascular hyper-reactivity, and immunologic dysregulation. Since Notch signaling is known to affect fibroblast homeostasis, angiogenesis, and lymphocyte development, we undertook this study to investigate the role of the Notch pathway in human and murine SSc. Methods. SSc was induced in BALB/c mice by subcutaneous injections of HOCl every day for 6 weeks. Notch activation was analyzed in tissues from mice with SSc and from patients with scleroderma. Mice with SSc were either treated or not treated with the gamma-secretase inhibitor DAPT, a specific inhibitor of the Notch pathway, and the severity of the disease was evaluated. Results. As previously described, mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase I antibodies. The Notch pathway was hyperactivated in the skin, lung, fibroblasts, and splenocytes of diseased mice and in skin biopsy samples from patients with scleroderma. ADAM17, a proteinase involved in Notch activation, was over-expressed in the skin of mice and patients in response to the local production of reactive oxygen species. In HOCl-injected mice, DAPT significantly reduced the development of skin and lung fibrosis, decreased skin fibroblast proliferation and ex vivo serum-induced endothelial H2O2 production, and abrogated the production of anti-DNA topoisomerase I antibodies. Conclusion. Our results show the pivotal role of the ADAM-17/Notch pathway in SSc following activation by reactive oxygen species. The inhibition of this pathway may represent a new treatment of this life-threatening disease.