Abstract
Microvesicles (MVs) are released by immune cells especially of the myeloid lineage upon stimulation with ATP on its cognate receptor P2X7, both in physiological and pathological conditions. In multiple sclerosis (MS) the role of MVs remains little investigated. We aimed to compare the release of MVs in peripheral blood monocytes from MS patients with healthy donors (HDs) and to see how current MS treatment may affect such a production. We also assessed the treatment effect on M1 and M2 monocyte polarization and on the inflammasome components. Spectrophotometric quantification was performed to compare monocyte-derived MVs from 20 untreated relapsing-remitting MS patients and 20 HDs and to evaluate the effect of different treatments. Subgroups of nine interferon-beta and of five teriflunomide-treated MS patients were evaluated at baseline and after 2, 6, and 12 months of treatment. Six MS patients taking Fingolimod, after switching from a first-line therapy, were included in the study and analyzed only at 12 months of treatment. MVs analysis revealed that monocytes from MS patients produced vesicles in higher amounts than controls. All treatments reduced vesicle production but only teriflunomide was associated with a downregulation of purinergic P2X7 receptor and inflammasome components expression. The therapies modulated mRNA expression of both M1 and M2 monocyte markers. Our results, suggesting new molecular targets for drugs currently used in MS, may potentially provide useful novel evidence to approach the disease.
Highlights
Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system (CNS) mainly in young adults with a complex predisposing genetic trait and plausibly needs a triggering environmental insult to promote the disease [1]
The amount of MVs was only found to be higher (p < 0.01) in multiple sclerosis (MS) patients compared to healthy donors (HDs) in unstimulated monocytes, while, upon stimulation with BzATP, only the HD monocytes exhibited a significant increase in fluorescence (p < 0.001)
As far as IFNb is concerned, a significant reduction of MV release (p < 0.05) was evident starting from the sixth month of treatment and it further decreased after 1 year of therapy (p < 0.01), whereas teriflunomide treated patients already showed a progressive reduction from the second month after the drug administration (p < 0.05), more significant after 6 months (p < 0.01) and even more after 1 year of treatment (p < 0.001)
Summary
Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system (CNS) mainly in young adults with a complex predisposing genetic trait and plausibly needs a triggering environmental insult (e.g., a viral infection) to promote the disease [1]. Multiple Sclerosis Treatments Affect Monocyte-Derived MV Production damage that leads to severe clinical disabilities. To this aim, a possible identification of biomarkers characterizing the different MS phenotypes or indicative of treatment response is crucial, representing a relevant target for research efforts. In recent years, increasing evidence has shown the role of extracellular vesicles (EVs) as mediators of several cellular functions, including cell–cell contact and transfer of secreted molecules [2]. Several studies report the importance of EVs (mainly MVs and EXOs) in CNS activities, e.g., in neuronal signaling and immunological responses. Glia and neurons secrete EVs and the recent literature indicates that intercellular communication by EVs has versatile functional impact in CNS homeostasis, including myelin formation, metabolic support, and immune defense [4]
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