Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species-Induced Mouse Model.
Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+and CD8+T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Université Sorbonne Paris Cité, 75014 Paris, France; and.|Laboratoire d'Immunologie Biologique, Hôpital Cochin, Assistance Publique-Hopitaux de Paris, 75679 Paris Cedex 14, France.
Florence
F
Morin
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Université Sorbonne Paris Cité, 75014 Paris, France; and.|Laboratoire d'Immunologie Biologique, Hôpital Cochin, Assistance Publique-Hopitaux de Paris, 75679 Paris Cedex 14, France.
Niloufar
N
Kavian
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Université Sorbonne Paris Cité, 75014 Paris, France; and.
Carole
C
Nicco
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Université Sorbonne Paris Cité, 75014 Paris, France; and.
Olivier
0000-0001-5697-7484
O
Cerles
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Université Sorbonne Paris Cité, 75014 Paris, France; and.
Christiane
C
Chéreau
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Université Sorbonne Paris Cité, 75014 Paris, France; and frederic.batteux@aphp.fr.|Laboratoire d'Immunologie Biologique, Hôpital Cochin, Assistance Publique-Hopitaux de Paris, 75679 Paris Cedex 14, France.
Frédéric
F
Batteux
D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use*; D001323:Autoantibodies; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001761:Bleomycin; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D006997:Hypochlorous Acid; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009534:Niclosamide / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000276:immunology; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000871:Anthelmintics; D001323:Autoantibodies; D016207:Cytokines; D017382:Reactive Oxygen Species; D001761:Bleomycin; D006997:Hypochlorous Acid; D009534:Niclosamide; D004264:DNA Topoisomerases, Type I