Tofacitinib restores psoriatic arthritis fibroblast-like synoviocytes function via autophagy and mitochondrial quality control modulation.

Autor: Silvagni E; Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona Ferrara, Italy., Missiroli S; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., Patergnani S; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., Boncompagni C; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., D'Ugo C; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., Garaffoni C; Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona Ferrara, Italy., Ciliento MS; Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona Ferrara, Italy; Department of Precision Medicine, University della Campania L. Vanvitelli, Naples, Italy., Lanza G; Anatomic Pathology, Department of Translational Medicine, University of Ferrara, Cona Ferrara, Italy., Bonora M; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., Gafà R; Anatomic Pathology, Department of Translational Medicine, University of Ferrara, Cona Ferrara, Italy., Perrone M; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., Bortoluzzi A; Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona Ferrara, Italy., Giorgi C; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy., Govoni M; Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona Ferrara, Italy., Scirè CA; IRCCS San Gerardo dei Tintori Foundation, Monza, Italy; School of Medicine, University of Milano Bicocca, Milan, Italy. Electronic address: carlo.scire@unimib.it., Pinton P; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara, Italy. Electronic address: paolo.pinton@unife.it.
Jazyk: angličtina
Zdroj: Journal of autoimmunity [J Autoimmun] 2024 Feb; Vol. 143, pp. 103159. Date of Electronic Publication: 2023 Dec 22.
DOI: 10.1016/j.jaut.2023.103159
Abstrakt: Objectives: To evaluate the in vitro effect of tofacitinib on autophagy activity of psoriatic arthritis (PsA) fibroblast-like synoviocytes (FLS), and to confirm its activity on inflammatory and invasive properties of FLS and synovial cells, deepening the impact on mitochondrial function.
Methods: FLS, peripheral blood mononuclear cells (PBMCs), and synovial cells from active PsA patients were cultured with tofacitinib 1 μM or vehicle control for 24 h. Autophagy was measured by Western blot and by fluorescence microscopy. Chemokines/cytokines released into culture supernatants were quantified by ELISA, while invasive properties of FLS by migration assays. Specific mitochondrial probes were adopted to measure intracellular reactive oxygen species (ROS), mitochondrial potential, morphology, turnover and mitophagy. Oxygen consumption rate (OCR), reflecting oxidative phosphorylation, was quantified using the Seahorse technology. Differences were determined by adopting the non-parametric Wilcoxon signed rank test.
Results: 18 patients with moderately-to-severely active PsA were enrolled. Tofacitinib significantly increased the levels of the autophagy markers LC3-II and ATG7 in PsA FLS compared to vehicle control, suggesting an increase in spontaneous autophagy activity; no effect was highlighted in PBMCs and synovial cells cultures. Tofacitinib reduced migration properties of PsA FLS, and reduced MCP-1 and IL-6 release into FLS and synovial cells cultures supernatants. Furthermore, tofacitinib decreased intracellular ROS production, increased basal OCR, ATP production and maximal respiratory capacity, and enhanced mitophagy and mitochondrial turnover.
Conclusions: The JAK inhibitor tofacitinib reduces the pro-invasive and pro-inflammatory properties of PsA FLS. Autophagy induction and mitochondrial quality control modulation by tofacitinib might contribute to FLS function restoration.
Competing Interests: Declaration of competing interest ES has received research support from AbbVie and Lilly and consulting/speaker's fees from AbbVie, Galapagos, Lilly, Novartis, Astra-Zeneca and Amgen. MG has received research support from AbbVie, Pfizer and Lilly and consulting/speaker's fees from AbbVie, Galapagos, Lilly, Alfa-Sigma, Astra-Zeneca and Amgen. The other authors declare no conflicts of interest.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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