MICROVESICLES: MESSENGERS AND MEDIATORS OF NEUROINFLAMMATION

Extracellular microvesicles (MVs) have been indicated as a way of intercellular communication and are emerging as new biomarkers of tissue damage. We have recently shown that microglia, upon in vitro activation, shed MVs containing pro-inflammatory cytokines. .Here we show that microglia derived MVs deliver a proinflammatory signal in vitro to neighbouring cells, microglia, astrocytes and also neuron. We also show that rodent and human cerebrospinal fluid (CSF) contain MVs of microglia origin, similar to those released in vitro by ATP-activated microglia. Flow cytometry analysis indicated increased levels of microglia-derived MVs in the CSF of mice intracerebrally injected with lentiviral vectors codifying for IFNγ or TNFα, a protocol known to induce dramatic activation of microglia/macrophages. These results represent the proof of principle that the amount of MVs in the CSF reflects the activation state of microglia in vivo and thus the extent of the inflammatory condition. In line with these data microglia MVs also increased in rodent CSF in the course of Experimental Autoimmune Encephalomyelitis (EAE), a widely used model for the inflammatory human disease multiple sclerosis (MS). In both chronic and relapsing EAE, the number of microglia-derived MVs was closely associated to disease course, increasing with EAE severity and decreasing with recovery. To verify if microglia MVs were similarly modulated in humans, we collected CSF from healthy donors, and MS patients. Elevated levels of microglia MVs were detected in the CSF collected from MS patients. To define whether microglia MVs contribute to neuroinflammation in vivo MVs were stereotaxically injected into the corpus callosum, a site usually devoid of inflammation. In addition, EAE was induced in acid spingomyelinase knock out mice, which are genetically impaired in MVs release. In vivo MVs administration induced an inflammatory response at the site of injection, while mice impaired in MVs shedding were protected from experimental. Altogether these findings identify microglia-derived MVs as novel biomarker and therapeutic target in brain inflammation.