Fibromyalgia (FM) is a common, rheumatic disorder characterized by chronic widespread pain as well as several other symptoms. The pathophysiology of this condition is still unclear, although it is established that central sensitization represents the neurobiologic basis of clinical manifestations. In recent years, mounting evidence has been accumulated about the contribute of resident microglia in the functional perturbation of pain-processing, key areas of brain involved in FM. Microglia represents a plastic, immune cells population able to shift its phenotype towards a pro-inflammatory state, influencing and disrupting through the release of several pro-inflammatory mediators, neural cells function of the involved brain areas. In FM, several pain-processing brain regions show an increased glutamatergic transmission, which has been related to an augmented pain perception. Activated microglia hyperexpresses glutaminase, an enzyme not only involved in the increased production of glutamate, the neurotransmitter responsible of neuronal excitotoxicity, but also in a further microglial pro-inflammatory activation. Indeed, glutaminase activity induces the production of pro-inflammatory extracellular vesicles (EVs) by activated microglia. EVs are mediators of intercellular communication, influencing the activity of target cells. Microglial cells exposed to EVs generated under neuroinflammatory conditions, shift towards a pro-inflammatory phenotype, promoting further expression and release of cytokines and other mediators. Moreover, in several neuroinflammatory and neurodegenerative conditions, microglial-derived EVs can be found on peripheral blood, in base of the capacity of EVs to diffuse towards lipid membranes, bypassing the blood-brain barrier. Aims of the present project are to investigate the role of activated microglia and of microglial-derived EVs in the pathophysiology and as potential biomarker of FM.
