Exosomal microRNAs associated with lung involvement in systemic sclerosis: potential diagnostic markers and therapeutic targets

<bold>Objectives.</bold> There is a pressing need to identify early biomarkers of lung involvement in systemic sclerosis (SSc) to start as soon as possible antifibrotic therapy. We aimed to identify exosomal microRNAs (miRNAs) that are differentially expressed between SSc patients with and without interstitial lung disease (ILD), and explore their association with fibrotic process. <bold>Methods.</bold> Plasma exosomes from 65 SSc patients with ILD (SSc-ILD, n=32), without ILD (SSc-no ILD, n=33) and 33 matched healthy donors were isolated. Small RNA sequencing followed by quantitative RT-PCR were used to identify and validate SSc-ILD-associated exosomal miRNAs. Moreover, the impact of SSc-ILD-derived exosomes on fibrotic process was investigated. <bold>Results.</bold> Among two cohorts of SSc patients, we found that the expression of four exosomal miRNAs (miR-744-5p, miR-584-5p, miR-1307-3p and miR-10b-5p) constitutes a molecular signature significantly associated with ILD. Deeper analysis revealed a correlation of these exosomal miRNAs with clinical parameters (DLCO, KCO) and a strong association with profibrotic processes (such as cellular senescence and apoptosis resistance). Finally, functional studies of exosomes from SSc-ILD patients highlighted their profibrotic property. <bold>Conclusions.</bold> Our study allowed us to identify potential biomarkers of SSc-ILD from plasma-derived exosomes, with a strong correlation with disease severity. The profibrotic property of exosomes from SSc-ILD patients suggested a prominent role of these vesicles on SSc severity.