MYELOID MICROVESICLES ARE A MARKER AND THERAPEUTIC TARGET FOR NEUROINFLAMMATION

Objective: Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of tissue damage. Our previous data indicate that reactive microglia/macrophages release MVs in vitro. Aim of the study was to evaluate whether MVs are released by microglia/macrophages in vivo and whether their number varies in brain inflammatory conditions, such as multiple sclerosis (MS). Methods: Electron and fluorescence microscopy and flow cytometry were used to detect myeloid MVs in the cerebrospinal fluid (CSF) of healthy controls, MS patients and rodents affected by experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Results: Myeloid MVs were detected in CSF of healthy controls. In both chronic and relapsing EAE mice, the concentration of myeloid MVs in the CSF was significantly increased and closely associated to disease course. Analysis of MVs in the CSF of 15 relapsing patients and 18 patients with clinical isolated syndrome, revealed higher levels of myeloid MVs than in 7 matched-age controls, indicating a clinical value of MVs as companion tool for disease diagnosis. Myeloid MVs were found to spread inflammatory signals both in vitro and in vivo, at the site of administration, while mice impaired in MV shedding were protected from EAE, suggesting a pathogenic role for MVs in the disease. Finally, FTY720, the first approved oral MS drug, significantly reduced the amount of MVs in the CSF of EAE treated mice. Interpretation: These findings identify myeloid MVs as valuable markers and therapeutic target of brain inflammation.