1. Academic Validation
  2. Effects of Ruxolitinib on fibrosis in preclinical models of systemic sclerosis

Effects of Ruxolitinib on fibrosis in preclinical models of systemic sclerosis

  • Int Immunopharmacol. 2023 Jan 23;116:109723. doi: 10.1016/j.intimp.2023.109723.
Nessrine Bellamri 1 Marie Lelong 1 Audrey Joannes 1 Erwan Le Tallec 2 Stéphane Jouneau 3 Laurent Vernhet 1 Alain Lescoat 2 Valérie Lecureur 4
Affiliations

Affiliations

  • 1 Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) -UMR_S 1085, 35000 Rennes, France.
  • 2 Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) -UMR_S 1085, 35000 Rennes, France; Department of Internal Medicine, Rennes University Hospital, 35000 Rennes, France.
  • 3 Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) -UMR_S 1085, 35000 Rennes, France; Department of Respiratory Diseases, Competence Center for Rare Pulmonary Diseases, Rennes University Hospital, 35000 Rennes, France.
  • 4 Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) -UMR_S 1085, 35000 Rennes, France. Electronic address: [email protected].
Abstract

Systemic sclerosis (SSc) is an autoimmune fibrotic disorder notably characterized by the production of antinuclear autoantibodies, which have been linked to an excess of apoptotic cells, normally eliminated by a macrophagic efferocytosis. As interferon (IFN) signature and phosphorylation of JAK-STAT proteins are hallmarks of SSc tissues, we tested the hypothesis that a JAK Inhibitor, ruxolitinib, targeting the IFN signaling, could improve efferocytosis of IFN-exposed human macrophages in vitro as well as skin and lung fibrosis. In vivo, BLM- and HOCl-induced skin thickness and fibrosis is associated with an increase of Caspase-3 positive dermal cells and a significant increase of IFN-stimulated genes expression. In BLM-SSc model, ruxolitinib prevented dermal thickness, fibrosis and significantly decreased the number of cleaved Caspase-3 cells in the dermis. Ruxolitinib also improved lung architecture and fibrosis although IFN signature was not entirely decreased by ruxolitinib. In vitro, ruxolitinib improves efferocytosis capacity of human monocyte-differentiated macrophages exposed to IFN-γ or IFN-β. In human fibroblasts derived from lung (HLF) biopsies isolated from patients with idiopathic pulmonary fibrosis, the reduced mRNA expression of typical TGF-β-activated markers by ruxolitinib was associated with a decrease of the phosphorylation of SMAD2 /3 and STAT3. Our finding supports the anti-fibrotic properties of ruxolitinib in a systemic SSc mouse model and in vitro in human lung fibroblasts.

Keywords

Fibrosis; Interferon; Lung fibroblast; Macrophage; Ruxolitinib; Systemic sclerosis.

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