Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis

Marzia Rossato, Alsya J. Affandi, Soley Thordardottir, Catharina G.K. Wichers, Marta Cossu, Jasper C.A. Broen, Frederique M. Moret, Lara Bossini-Castillo, Eleni Chouri, Lenny van Bon, Femke Wolters, Wioleta Marut, Maarten van der Kroef, Sandra Silva-Cardoso, Cornelis P.J. Bekker, Harry Dolstra, Jacob M. van Laar, Javier Martin, Joel A.G. van Roon, Kris A. ReedquistLorenzo Beretta, Timothy R.D.J. Radstake

Research output: Contribution to journalArticle

Abstract

Objective: Plasmacytoid dendritic cells (PDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to PDC dysregulation and a persistent type I IFN signature are largely unexplored, especially in patients with systemic sclerosis (SSc), a disease in which PDCs infiltrate fibrotic skin lesions and produce higher levels of IFNα than those in healthy controls. This study was undertaken to investigate potential microRNA (miRNA)–mediated epigenetic mechanisms underlying PDC dysregulation and type I IFN production in SSc. Methods: We performed miRNA expression profiling and validation in highly purified PDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miRNA-618 (miR-618) on PDC biology were identified by overexpression in healthy PDCs. Results: Expression of miR-618 was up-regulated in PDCs from SSc patients, including those with early disease who did not present with skin fibrosis. IFN regulatory factor 8, a crucial transcription factor for PDC development and activation, was identified as a target of miR-618. Overexpression of miR-618 reduced the development of PDCs from CD34+ cells in vitro and enhanced their ability to secrete IFNα, mimicking the PDC phenotype observed in SSc patients. Conclusion: Up-regulation of miR-618 suppresses the development of PDCs and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of PDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.

Original languageEnglish
Pages (from-to)1891-1902
Number of pages12
JournalArthritis and Rheumatology
Volume69
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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    Rossato, M., Affandi, A. J., Thordardottir, S., Wichers, C. G. K., Cossu, M., Broen, J. C. A., Moret, F. M., Bossini-Castillo, L., Chouri, E., van Bon, L., Wolters, F., Marut, W., van der Kroef, M., Silva-Cardoso, S., Bekker, C. P. J., Dolstra, H., van Laar, J. M., Martin, J., van Roon, J. A. G., ... Radstake, T. R. D. J. (2017). Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis. Arthritis and Rheumatology, 69(9), 1891-1902. https://doi.org/10.1002/art.40163