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.
Understanding the involvement of neuroinflammatory process in FM may represent the biggest step forward in the knowledge about the pathogenesis of this condition, considering the mounting evidence in support to this hypothesis. Despite the large efforts that have been dedicated to study FM pathogenesis, this disease can still be considered of unknown etiology, with the obvious, consequential uncertainties both in diagnostic process and in treatment. From patients' perspective, this uncertainty contributed to the still diffuse idea of FM as an "imaginary" condition or secondary to a depression(23). The lack of a diagnostic biomarker is a big unmet need in FM. Indeed, in spite of the clear evidence of brain imaging abnormalities, sophisticated techniques such as functional MRI or PET are not readly available in clinical practice, especially taking in account the high prevalence of the disease in the general population. Moreover, FM presents a broad differential diagnosis, which complicates the physician¿s task, considering that the diagnosis is still clinical. A serum biomarker would represent the ideal tool in this context. EVs are gaining attention for their potential utility in several conditions, as stated above. In oncology, EVs evaluation in the diagnosis of cancer achieved the term of liquid biopsy to describe the high accuracy of the technique(24). Similarly, strong proof-of-concept studies demonstrated the efficiency of blood neural-derived EVs in the diagnosis of neurodegenerative disorders. Studying EVs deriving from brain cells on blood represents de facto an ante-mortem test of the abnormal processes that may occur in the CNS(25). In the last five years, there has been an increasing report of studies on EVs in neuroinflammatory process. In the same lag of time, mounting evidence has been accumulated on the involvement of neuroinflammation in FM pathogenesis. However, to the best of our knowledge, this project would represent the first study investigating the involvement of EVs in FM neuroinflammatory process, opening a brand-new research topic with several potential repercussions. A part the obvious potential as biomarker, the demonstration of EVs and neuroinflammation involvement in FM would have potential therapeutic implications. FM is a condition difficult, and often frustrating to treat. The evidence for symptomatic benefit from all the currently available medication is modest, and this is the consequence of the still undetermined pathophysiology of the disease(26). Targeting the neuroinflammatory process may represent a successful strategy in this context. For example, in animal model of depression, which could share several neuroinflammatory aspects with FM, the inhibition of glutaminase, a key enzyme of neuroinflammation and EVs production, showed to abolish depressive behaviours(27). This, as well as similar approaches, would offer for the first time, a potential range of etiologic treatment targets in FM. Central sensitization is a key feature of FM, in common with other CSSs. The demonstration of the role of neuroinflammation in the pain-perception augmentation of FM could be extended consequentially to the other CSSs, opening, in a similar fashion, to new investigations and offering, likewise, new diagnostic and therapeutic perspectives also in these conditions. At last, the demonstration of a discriminative capacity of EVs in FM with cognitive symptoms respect to MCI could represent an useful tool in the clinical practice for patients with severe cognitive impairment or those who need reassurance that they are not developing dementia.
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