Implication of miR-126 and miR-139-5p in Plasmacytoid Dendritic Cell Dysregulation in Systemic Sclerosis.

Eleni Chouri,Lenny Van Bon,Catharina G K Wichers,Sandra C Silva-Cardoso,Lorenzo Beretta,Tiago Carvalheiro,Maarten Van Der Kroef,Boudewijn M T Burgering,Marzia Rossato,Alsya J Affandi,Aridaman Pandit,Joel A G Van Roon,Chiara Angiolilli,Maojie Wang,Marta Cossu,Cornelis P J Bekker,Timothy R D J Radstake,Maarten R Hillen

doi:10.3390/jcm10030491

Abstract

Compelling evidence shows the involvement of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc) pathogenesis. This study investigated whether microRNAs (miRNAs) are involved in the dysregulation of pDCs in SSc patients already at early stages. RNA from circulating pDCs was isolated from two independent cohorts of SSc patients with different disease phenotypes, and individuals with Raynaud’s phenomenon, for microRNA profiling and RNA-sequencing analysis. Proteomic analysis was exploited to identify novel direct miRNA targets at the protein level. Twelve and fifteen miRNAs were differentially expressed in at least one group of patients compared to healthy controls in discovery cohort I and II, respectively. Of note, miR-126 and miR-139-5p were upregulated in both preclinical and definite SSc patients and correlated with the expression of type I interferon (IFN)-responsive genes. Toll-like receptor 9 (TLR9) stimulation of healthy pDCs upregulated the expression of both miRNAs, similarly to what was observed in patients. The proteomic analysis identified USP24 as a novel target of miR-139-5p. The expression level of USP24 was inversely correlated with miR-139-5p expression in SSc patients and induced by TLR9 stimulation in healthy pDCs. These findings demonstrated that the miRNA profile is altered in pDCs of SSc patients already at early stages of the disease and indicate their potential contribution to pDC activation observed in patients.

Highlights

Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by connective tissue fibrosis in the skin and internal organs
Compelling evidence has demonstrated the role of plasmacytoid dendritic cells (pDCs) in SSc pathogenesis [5,6], and it showed that the depletion of pDCs ameliorates skin fibrosis in a mouse model of scleroderma [6]
MiR-126 and miR-139-5p were upregulated in the preclinical SSc patients, and they displayed aberrant expression in later stages of the disease, indicating that these miRNAs might be associated with the alterations of pDC that underpin SSc development

Summary

Introduction

Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by connective tissue fibrosis in the skin and internal organs. The presence of inflammatory hallmarks, including the type I interferon (IFN) signature and the characteristic autoantibody profile fingerprint, further emphasizes the implication of immune dysregulation in these patients [1,3,4]. PDCs are the major interferon producing cells, suggesting their role in perpetuating the type I IFN signature characterizing these patients. Kim et al showed that serum from SSc patients, containing autoantibodies, induced pDC activation and interferon-α (IFN-α) production from healthy cells [7] via the uptake of immune complexes through the Fc-gamma (Fcγ) receptor and the interaction with Toll-like receptors (TLR) [7,8]. PDCs infiltrate the skin of SSc patients, where they release IFN-α and CXCL4 [5,6]. The depletion of pDCs reduced skin fibrosis in a mouse model of scleroderma with established disease, and their depletion could prevent disease [6]

Methods

Results

Conclusion