Article

Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

Istituto Pasteur, Fondazione Cenci Bolognetti, Rome, Italy.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 03/2010; 35(7):1550-9. DOI: 10.1038/npp.2010.26
Source: PubMed

ABSTRACT

Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-alpha, interleukin-1-beta, and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A(1) receptors (A(1)R) with the specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) abolishes CX3CL1-mediated rescue of neuronal excitotoxic death and that CX3CL1 induces the release of adenosine from microglia. In this study, we show that the presence of extracellular adenosine is mandatory for the neurotrophic effect of CX3CL1 as reducing adenosine levels in hippocampal cultures, by adenosine deaminase treatment, strongly impairs CX3CL1-mediated neuroprotection. Furthermore, we confirm the predominant role of microglia in mediating the neuronal effects of CX3CL1, because the selective depletion of microglia from hippocampal cultures treated with clodronate-filled liposomes causes the complete loss of effect of CX3CL1. We also show that hippocampal neurons obtained from A(1)R(-/-) mice are not protected by CX3CL1 whereas A(2A)R(-/-) neurons are. The requirement of functional A(1)R for neuroprotection is not unique for CX3CL1 as A(1)R(-/-) hippocampal neurons are not rescued from Glu-induced cell death by other neurotrophins such as brain-derived neurotrophic factor and erythropoietin, which are fully active on wt neurons.

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    • "CX3CL1 protects neurons from Glu excitotoxicity both in in vitro and in vivo models with mechanisms fully dependent on A 1 R (Lauro et al., 2008, 2010; Cipriani et al., 2011) and partially dependent on A 3 R (Rosito et al., 2014). Indeed CX3CL1, acting on microglia, is able to increase extracellular adenosine derived from released adenosine triphosphate (ATP), since this effect is abolished in the presence of specific inhibitor of ectonucleotidases (AOPCP) but not by the inhibitor of equilibrative transport (NBTI) (Lauro et al., 2008, 2010). Upon Glu toxic challenge, we have shown that CX3CL1 is able to increase Glu removal from synaptic cleft by enhancing excitatory amino acid transporter GLT- 1 expression and function, specifically on astrocytes, with a mechanism that depends on A 1 R activation (Catalano et al. 2013). "

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    • "One way to further understand how inflammation and other seizure-induced brain pathologies are related is to study single potential signaling pathways between microglia and neurons. Various inflammatory mediators which are known to regulate microglial activation (Cardona et al., 2006; D'Haese et al., 2012), have also been implicated in adult neurogenesis and synaptic transmission (Butovsky et al., 2006; Lauro et al., 2010; Scianni et al., 2013). Fractalkine is an inflammatory chemokine secreted by neurons and astrocytes. "
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    • "Catalano et al. (2013), in fact, demonstrated that CX3CL1, acting on microglia, induced the production and release of soluble factors that exerted their effects on astrocytes, inducing the functional up regulation and the increased expression of the excitatory amino acid transporter GLT-1. As already reported in in vitro and in vivo systems (Lauro et al., 2010; Cipriani et al., 2011), this cross-talk requires the “permissive” presence of adenosine, specifically acting on astrocyte A1R (Catalano et al., 2013). These data demonstrated for the first time a role for astrocytes in mediating the neuroprotection induced by CX3CL1/CX3CR1 signaling between microglia and neurons. "
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