The importance of microglia-astrocytes cross-talk in the maintenance of brain homeostasis, and in granting neuronal functionality represent a new field of research that is worth to be investigated in order to identify new target to be considered when treating brain disorders. Interplay between cells can be achieved by the release of soluble factors, by cell-to-cell adhesion molecules but also through the exchange of molecular "cargo" via extracellular vesicles such as microvesiscles (MVs). In recent years, the role of chemokines in participating in the cross-talk between cells of the brain parenchyma has also emerged, and in particular we found that chemokine CXCL16, physiologically expressed in the brain, represent an endogenous molecule that counteract brain damage upon ischemic insult. Moreover, we demonstrated that CXCL16, exogenously admninistrated, acts on astrocytes inducing the release of "soluble" mediators that concurr to reduce glutamate excitotoxic neuronal damage.Further we found that CXCL16 is able to contrast microglia polarization towards an inflammatory phenotype. Since glutamate excitotoxicity and inflammatory conditions are both events that occur in several brain disorders, we want to investigate the possibility that MVs, released upon CXCL16 treatment of microglia or astrocytes, might represent a tool to contrast these events; in addition we want to investigate if intranasal administration of such MVs might be able to contrast LPS induced neuroinflammation.
Brain disorders are one of the greatest health challenges. Around 165 million Europeans are living with a brain disorder. The global cost to European healthcare budgets is estimated to be €800 billion per year, and this is expected to increase further as Europe's population ages and becomes more susceptible to brain disorders. Currently, 16% of the European population is over 65, and this figure is expected to reach 25% by 2030. Existing treatments for brain diseases are very limited, and only treat the symptoms, rather than addressing the cause. However, despite different etiologies are responsible for neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease) or acute brain disorders (such as traumatic brain injuries or ischemia), same common mechanisms that impact brain disorders' progression are glutamate excitotoxicity and neuroinflammation, both occurring during the different pathologies. Therefore, it would be important to identify specific treatment that might impact on both these mechanisms, in order to limit brain damage and to slow down disease progression. For these reasons it is of utmost interest to identify new strategies to prevent/limit inflammation or glutamate excitotoxicity in order to slow the progression of brain disorders.
In our lab, for the first time, we have highlighted the expression of CXCL16 and its receptor CXCR6 on cells of the brain parenchyma, such as neurons, microglia and astrocytes, and found that CXCL16 represent an endogenous signal that counteract brain damage upon toxic stimuli such as ischemia, or glutamate excitotoxicity.. Moreover we found that exogenous administration of soluble CXCL16, is able to reduce in significative way brain damage, also through the release of "soluble factors" from astrocytes, and we have demonstrated that CXCL16 is able to counteract inflammatory microglia phenotype. Considering all these findings, we hypotesize that CXCL16 is molecules that might represent a putative drug to counteract both inflammation and excitotoxicity.
The time for developing CNS drugs is normally much longer than for non-CNS drugs. Clinical trials of CNS drugs become challenging because of the complexity of the brain, side effects and the impermeability of the blood-brain barrier (BBB). In addition to the complexity of brain diseases, the lack of efficient technologies to deliver drugs across the BBB hinders CNS drug development. Anti-inflammatory drugs that could be used to target microglia cells in the brain, unfortunately are unable to cross the BBB. However, recently it has been shown that exosomes, administered intranasally, are potential delivery vehicles for these therapeutic agents in the brain (1). Thus non-invasive intranasal administration of microvescicles (MV), derived by glial cells treated with CXCL16, could represent a valuable strategy to be exploit to counteract brain damage.
In these 12 months projects, we will produce preliminary results to explore the ability of CXCL16 derived microglia MVs to modulate microglia and astrocytes activity in vitro, and we will test the efficacy of these CXCL16 MVs to counteract brain inflammation (LPS administration model) also in vivo, by intranasal administration. The results obtained in this project will pave the way for future investigations on the use of MVs from CXCL16 treated microglia or astrocytic cells to counteract brain damage with a excitotoxic and inflammatory component in acute brain disorder, such as ischemia, or neurodegenerative disorders such as Alzheimer's disease.
Reference:
1-Lakhal and Wood (2011) Mol Ther. 19:1754-6
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