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 journalArticleAcademicpeer-review


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 & rheumatology
Issue number9
Publication statusPublished - Sep 2017

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