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Article Dans Une Revue International Immunopharmacology Année : 2023

Effects of Ruxolitinib on fibrosis in preclinical models of systemic sclerosis

Résumé

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.
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Dates et versions

hal-03968457 , version 1 (17-03-2023)

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Paternité - Pas d'utilisation commerciale

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Nessrine Bellamri, Marie Lelong, Audrey Joannes, Erwan Le Tallec, Stéphane Jouneau, et al.. Effects of Ruxolitinib on fibrosis in preclinical models of systemic sclerosis. International Immunopharmacology, 2023, 116, pp.109723. ⟨10.1016/j.intimp.2023.109723⟩. ⟨hal-03968457⟩
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