Targeting ADAM‐17/notch signaling abrogates the development of systemic sclerosis in a murine model

Abstract

Objective. Systemic sclerosis (SSc) is characterized by the fibrosis of various organs, vascular hyperreactivity, 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 ␥-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. ADAM-17, a proteinase involved in Notch activation, was overexpressed 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 H 2 O 2 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 lifethreatening disease.

CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

“…Simultaneously, intradermal ROS can induce the synthesis of the metalloprotease ADAM17, which is a trigger protease in the first step of Notch activation and cleaves the ectodomain of the Notch receptor. ROS-induced ADAM17 could be another major factor for activation of the Notch pathway in systemic sclerosis [97,98]. In this way, ROS might function as a dual trigger of Nrf2-Notch crosstalk.…”

Arsenic Trioxide Prevents Murine Sclerodermatous Graft-versus-Host Disease

“…They were given humane care, according to the guidelines of our institution (Université Paris Descartes). All cells were cultured as previously reported (18). All chemicals were from Sigma-Aldrich (SaintQuentin Fallavier, France).…”

Cellular and molecular mechanisms in the pathophysiology of systemic sclerosis

“…Attenuated fibrosis in SCID mice argued for a significant synergistic role of the immune systems via generation of advanced oxidation protein products (AOPP), responsible for profibrotic effects on fibroblasts in this model [91]. Many signaling pathways have been implicated in the pathophysiology of this experimental disease, comprising the cannabinoids [92], the Notch proteins activated by metalloprotease ADAM-17 [93], PDGF [94], and angiotensin II [95]. Interestingly, treatment of HOCl-intoxicated mice by pro-oxidants such as arsenic trioxide (As 2 O 3 ) or the organotellurique catalyst ([PHTE] 2 NQ) permitted to ''kill'' activated fibroblasts and therefore reduce skin and lung fibrosis in this murine model of SSc [96].…”