Abstract
Microvesicles (MVs) are membrane particles of 200–500 nm released by all cell types constitutively. MVs of myeloid origin are found increased in the cerebrospinal fluid (CSF) of patients suffering from neuroinflammatory disorders, although the factors triggering their production have never been defined. Here, we report that both pro- and anti-inflammatory cytokines, specifically interferon-γ and interleukin-4, are equally able to stimulate the production of MVs from microglia cells and monocytes. Additionally, we found this process to be independent from the best characterized molecular pathway so far described for membrane shedding, which is centered on the purinergic receptor P2X7, whose activation by high concentrations of extracellular ATP (exATP) results in membrane blebbing operated by the secreted enzyme acid sphingomyelinase (ASMase). Moreover, a potent inhibitor of ASMase, injected in a mouse model of multiple sclerosis, failed to reduce the number of MVs in their CSF. This suggests that cytokines, rather than exATP, may exert a long-term control of MV production in the context of chronic inflammation, where both pro- and anti-inflammatory factors play coordinated roles.
Highlights
Extracellular vesicles (EVs) are microparticles produced by all cell types in physiological and pathological conditions
In order to assess the role of extracellular ATP (exATP) in the release of MVs during inflammation of the nervous system, EAE mice were treated with imipramine and the disease course was daily monitored with respect to that of vehicle-injected animals
Imipramine did modify neither the clinical evolution of the disease (Figure 1A) nor the amount of myeloid cell-derived MVs in the cerebrospinal fluid (CSF) of treated versus vehicle-injected controls (Figures 1B,C). These results suggest that exATP probably has a minor role in the generation and/ or maintaining the MV production elevated during chronic neuroinflammation
Summary
Extracellular vesicles (EVs) are microparticles produced by all cell types in physiological and pathological conditions. Two main types of EVs have been described, microvesicles (MVs) and exosomes, whose differences reside in the dimension as well as in the mechanisms underlying their generation. The molecular mechanisms participating in EV biogenesis are known only in part. As far as their functions are concerned, two main hypotheses have been proposed: (i) EVs may act as a system for cell-to-cell communication by shuttling active biomolecules among cells, (ii) they could serve as vehicles for discharging damaged molecules (lipids and proteins) out of the cell, lightening the ubiquitin-proteasomal system as well as lysosomes in case of overload. The interest for EVs increased exponentially starting from the observation that in many different diseases their number is significantly increased
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