title: Leflunomide prevents ROS-induced systemic fibrosis in mice.
abstract: Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy and immunological abnormalities. Recent insights into the polarization of macrophages in scleroderma and into the implication of STAT6 and KLF4 in this process have prompted us to investigate the effects of the inhibition of STAT6 signaling pathway by leflunomide in mice. SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) or bleomycin. Mice were treated (or not) every other day, for 4 or 6 weeks, by leflunomide. 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 auto-antibodies. STAT6 pathway was hyperactivated and KLF4 was overexpressed in the skin and the lungs of diseased mice. Their inhibition by leflunomide prevented skin and lung fibrosis. Moreover, the hyperproliferative and pro-oxidative phenotype of skin and lung fibroblasts was reversed by leflunomide. Beneficial immunological effects of leflunomide were associated with decreased activation of CD4+ and CD8+ T cells, B cell activation, decreased auto-antibodies production and restored polarization of macrophages in the spleen. The improvement provided by leflunomide in both mouse models of SSc provides a rationale for the evaluation of this immunomodulating drug in the management of patients affected by this disease.
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, 75679 Paris cedex 14, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Morin
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, 75679 Paris cedex 14, France.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cerles
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.affiliation: INSERM U1016, Institut Cochin, Cnrs, UMR8104, Université Paris Descartes Sorbonne Paris Cité, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, 75679 Paris cedex 14, France. Electronic address: frederic.batteux@aphp.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D001761:Bleomycin / Q000008:administration & dosage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D006997:Hypochlorous Acid / Q000008:administration & dosage; D007165:Immunosuppression Therapy; D007555:Isoxazoles / Q000627:therapeutic use*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077339:Leflunomide; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*
chemical_list: D018501:Antirheumatic Agents; D001323:Autoantibodies; D007555:Isoxazoles; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017382:Reactive Oxygen Species; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D001761:Bleomycin; D006997:Hypochlorous Acid; D000077339:Leflunomide
keywords: Fibrosis; Leflunomide; Macrophages; STAT6; Systemic sclerosis