Imbalance of the Vanin-1 Pathway in Systemic Sclerosis.

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/- mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.

• Authors: Niloufar Kavian, Souad Mehlal, Wioleta Marut, Amélie Servettaz, Caroline Giessner, Christophe Bourges, Carole Nicco, Christiane Chéreau, Hervé Lemaréchal, Marie-Flore Dutilh, Olivier Cerles, Philippe Guilpain, Vincent Vuiblet, Sandrine Chouzenoux, Franck Galland, Isabelle Quere, Bernard Weill, Philippe Naquet, Frédéric Batteux
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 197 Issue 8 Pg. 3326-3335 (10 15 2016) ISSN: 1550-6606 [Electronic] United States
• PMID: 27647831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• GPI-Linked Proteins
• Pantothenic Acid
• Amidohydrolases
• pantetheinase

Topics

• Amidohydrolases (metabolism)
• Animals
• Female
• GPI-Linked Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Pantothenic Acid (metabolism)
• Scleroderma, Systemic (metabolism)