Background Inflammatory myopathies (IM) are a heterogeneous group of disorders characterized by autoimmune inflammatory destruction of skeletal muscles. It is many times associated with lung, skin and joint involvement. Identifying biomarkers that can differentiate IM from other muscle disorders may elucidate the pathophysiology of IM, guide novel therapies, monitor disease activity/response to treatments and predict prognosis. Exosomes are membrane-bound nanovesicles with diameters of 30-150 nm that contain multiple proteins, nucleic acid, lipids and other molecules in a tissue- and cell-specific manner. Exosomes are secreted by a large variety of cells, play major roles in cell-cell interactions, and have recently emerged as circulating biomarkers in a variety of pathological conditions, including several autoimmune diseases.
Objectives To characterize exosomes from serum of IM patients, analyze protein expression and study their potential mediators of disease pathologies.
Methods Serum was collected from patients suffering from IM(n=5) and from patients suffering from Becker (BMD) and Duchenne (DMD) muscular dystrophies (n=6). Exosomes were isolated by Exoquick precipitation and analyzed for size distribution and by nanoparticle tracking analysis (NTA) and by Western blot for exosome markers. The effects of the isolated EVs on human satellite cell proliferation and differentiation and macrophage activation were examined.
Results Exosomes from IM patients decreased human satellite cell proliferation (51%, P<0.01) and inhibited their myogenic differentiation as indicated by lower fusion index (24% inhibition, P<0.01) and expression of myosin heavy chain (72% inhibition, P<0.001). Similar results were obtained also with exosomes derived from DMD and BMD patients; however, their inhibitory effect were more pronounced on MyoG expression. Treatment of macrophages with exosomes from IM patients significantly increased the expression of IL-10 (3-fold, P<0.001), compared to exosomes of healthy controls and DMD patients. Another significant difference was in the expression of signaling molecules: Thus, exosomes from BMD patients increased the phosphorylation of Erk and p38, whereas a smaller effect was induced by IM exosomes.
Conclusion Exosomes from IM patients decrease satellite cell proliferation and myogenic differentiation compared to healthy exosomes. In addition, these exosomes increased the expression of IL-10 in macrophages. These effects are unique to exosomes of IM patients compared to muscular dystrophies. These promising results suggest that serum exosomes should be further investigated as a novel biomarker with potential therapeutic implications.
Disclosure of Interests Shaye Kivity Speakers bureau: BI, Abbvie, Lilly, Pfizer, Janssen, Neopharm, Grant/research support from: Sobi, Haya Kravitz: None declared, Coral Cohen: None declared, Darya Margoulis: None declared, Moshe Amar: None declared, Gila Kazimirsky: None declared, David Ozeri Speakers bureau: Neopharm, Consultant of: Abbvie, Amir Dori Grant/research support from: Biogen, Chaya Brodie Grant/research support from: Biogen.
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