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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 IFN\u03b1 than those in healthy controls. This study was undertaken to investigate potential microRNA (miRNA)\u2013mediated epigenetic mechanisms underlying PDC dysregulation and type I IFN production in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010618 (miR\u2010618) on PDC biology were identified by overexpression in healthy PDCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of miR\u2010618 was up\u2010regulated 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\u2010618. Overexpression of miR\u2010618 reduced the development of PDCs from CD34+ cells in vitro and enhanced their ability to secrete IFN\u03b1, mimicking the PDC phenotype observed in SSc patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Up\u2010regulation of miR\u2010618 suppresses the development of PDCs and increases their ability to secrete IFN\u03b1, 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\u2010618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40163","type":"journal-article","created":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T11:12:45Z","timestamp":1495797165000},"page":"1891-1902","source":"Crossref","is-referenced-by-count":73,"title":["Association of MicroRNA\u2010618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis"],"prefix":"10.1002","volume":"69","author":[{"given":"Marzia","family":"Rossato","sequence":"first","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0859-2322","authenticated-orcid":false,"given":"Alsya J.","family":"Affandi","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soley","family":"Thordardottir","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina G. 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