TY - JOUR
T1 - Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis
AU - Rossato, Marzia
AU - Affandi, Alsya J
AU - Thordardottir, Soley
AU - Wichers, Catharina G K
AU - Cossu, Marta
AU - Broen, Jasper C A
AU - Moret, Frederique M
AU - Bossini-Castillo, Lara
AU - Chouri, Eleni
AU - van Bon, Lenny
AU - Wolters, Femke
AU - Marut, Wioleta
AU - van der Kroef, Maarten
AU - Silva-Cardoso, Sandra
AU - Bekker, Cornelis P J
AU - Dolstra, Harry
AU - van Laar, Jacob M
AU - Martin, Javier
AU - van Roon, Joel A G
AU - Reedquist, Kris A
AU - Beretta, Lorenzo
AU - Radstake, Timothy R D J
N1 - © 2017, American College of Rheumatology.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
KW - Adult
KW - Antigens, CD34/metabolism
KW - Case-Control Studies
KW - Dendritic Cells/metabolism
KW - Epigenesis, Genetic
KW - Female
KW - Humans
KW - Interferon-alpha/metabolism
KW - Male
KW - MicroRNAs/blood
KW - Middle Aged
KW - Scleroderma, Systemic/blood
KW - Up-Regulation
U2 - https://doi.org/10.1002/art.40163
DO - https://doi.org/10.1002/art.40163
M3 - Article
C2 - 28556560
SN - 2326-5191
VL - 69
SP - 1891
EP - 1902
JO - Arthritis & Rheumatology
JF - Arthritis & Rheumatology
IS - 9
ER -