Fractalkine-induced activation of the Phosphotidylinositol-3 kinase pathway attenuates microglial activation in vivo and in vitro

Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin 2, Ireland.
Journal of Neurochemistry (Impact Factor: 4.28). 08/2009; 110(5):1547-56. DOI: 10.1111/j.1471-4159.2009.06253.x
Source: PubMed


Several neurodegenerative disorders are associated with evidence of inflammation, one feature of which is increased activation of microglia, the most likely cellular source of inflammatory cytokines like interleukin-1beta. It is now recognized that interaction of microglia with other cells contributes to maintenance of microglia in a quiescent state and the complementary distribution of the chemokine, fractalkine (CX(3)CL1) on neurons and its receptor (CX(3)CR1) on microglia, suggests that this interaction may play a role in modulating microglial activation. Here we demonstrate that both soluble and membrane-bound fractalkine attenuate lipopolysaccharide-induced microglial activation in vitro. We also show that fractalkine expression is reduced in the brain of aged rats and this is accompanied by an age-related increase in microglial activation. Treatment of aged rats with fractalkine attenuates the age-related increase in microglial activation and the evidence indicates that fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway is required to maintain microglia in a quiescent state both in vivo and in vitro.

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    • "CX3CL1 decreased in the brain of aged mice possibly due to neuronal loss, and this change is accompanied by an altered effector state of microglia (Lyons et al., 2009; Wynne et al., 2010; Bachstetter et al., 2011). In aged mice, the response to systemic infection is amplified by the microglia effector response: LPS administration evokes an increased IL-1β and a reduced TGFβ expression, in comparison with young adult animals (Wynne et al., 2010). "
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    ABSTRACT: Since the initial cloning of fractalkine/CX3CL1, it was proposed that the only known member of the CX3C or δ subfamily of chemotactic cytokines could play some significant role in the nervous system, due to its high expression on neurons. The pivotal description of the localization of the unique CX3CL1 receptor, CX3CR1, on microglial cells, firmed up by the generation of cx3cr1(GFP/GFP) mice, opened the road to the hypothesis of some specific key interactions between microglia and neurons mediated by this pair. This expectation has been indeed supported by recent exciting evidence indicating that CX3CL1-mediated microglia-neuron interaction modulates basic physiological activities during development, adulthood and aging, including: synaptic pruning; promoting survival of neurons and neural precursors; modulating synaptic transmission and plasticity; enhancing synapse and network maturation; and facilitating the establishment of neuropathic pain circuits. Beyond playing such fascinating roles in physiological conditions, CX3CL1 signaling has been implicated in different neuropathologies. Early papers demonstrated that the levels of CX3CL1 may be modulated by various toxic stimuli in vitro and that CX3CL1 signaling is positively or negatively regulated in EAE and MS, in HIV infection and LPS challenge, in epilepsy, in brain tumors, and in other neuropathologies. In this review we focus on the experimental evidence of CX3CL1 involvement in neuroprotection and survey the common molecular and cellular mechanisms described in different brain diseases.
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    • "Consistent with this hypothesis, ADAM17-mediated increase in soluble CX 3 CL1 is observed in multiple settings of glutamatergic neurotransmission where the chemokine is suggested to perform a neuroprotective function (Chapman et al., 2000; Tsou et al., 2001; Erichsen et al., 2003; Limatola et al., 2005; Ragozzino et al., 2006; Lauro et al., 2010; Pabon et al., 2011). At levels reached during inflammatory conditions, CX 3 CL1 signaling has previously been associated with activation of pro-survival and anti-apoptotic pathways through phosphorylation of molecules such as Akt, as well as activation of MAP kinases such as p-38 and Erk1/2 (p44/42; Maciejewski-Lenoir et al., 1999; Meucci et al., 2000; Cambien et al., 2001; Deiva et al., 2004; Klosowska et al., 2009; Lyons et al., 2009). "
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    ABSTRACT: Several cytokines and chemokines are now known to play normal physiological roles in the brain where they act as key regulators of communication between neurons, glia and microglia. In particular, cytokines and chemokines can affect cardinal cellular and molecular processes of hippocampal-dependent long-term memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis. The chemokine, CX3CL1 (fractalkine), has been shown to modulate synaptic transmission and long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus. Here, we confirm widespread expression of CX3CL1 on mature neurons in the adult rat hippocampus. We report an up-regulation in CX3CL1 protein expression in the CA1, CA3 and dentate gyrus of the rat hippocampus 2 h after spatial learning in the water maze task. Moreover, the same temporal increase in CX3CL1 was evident following long-term potentiation-inducing theta-burst stimulation in the dentate gyrus. At physiologically relevant concentrations, CX3CL1 inhibited LTP maintenance in the dentate gyrus. This attenuation in dentate LTP was lost in the presence of GABAA receptor/chloride channel antagonism. CX3CL1 also had opposing actions on glutamate-mediated rise in intracellular calcium in hippocampal organotypic slice cultures in the presence and absence of GABAA receptor/chloride channel blockade. Using primary dissociated hippocampal cultures, we established that CX3CL1 reduces glutamate-mediated intracellular calcium rises in both neurons and glia in a dose dependent manner. In conclusion, CX3CL1 is up-regulated in the hippocampus during a brief temporal window following spatial learning the purpose of which may be to regulate glutamate-mediated neurotransmission tone. Our data supports a possible role for this chemokine in the protective plasticity process of synaptic scaling.
    Full-text · Article · Jul 2014 · Frontiers in Cellular Neuroscience
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    • "Thus, FKN may play a role in the homeostatic suppression of microglial activation. The seemingly natural decline in neuronally expressed FKN in the hippocampus of aged animals [66] might contribute to increased microglial activation. If the same occurs in humans, this decrease in FKN expression over time could contribute to several cognitive and neurodegenerative disorders that are more common in the elderly. "
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    ABSTRACT: An essential aspect of normal brain function is the bidirectional interaction and communication between neurons and neighbouring glial cells. To this end, the brain has evolved ligand-receptor partnerships that facilitate crosstalk between different cell types. The chemokine, fractalkine (FKN), is expressed on neuronal cells, and its receptor, CX3CR1, is predominantly expressed on microglia. This review focuses on several important functional roles for FKN/CX3CR1 in both health and disease of the central nervous system. It has been posited that FKN is involved in microglial infiltration of the brain during development. Microglia, in turn, are implicated in the developmental synaptic pruning that occurs during brain maturation. The abundance of FKN on mature hippocampal neurons suggests a homeostatic non-inflammatory role in mechanisms of learning and memory. There is substantial evidence describing a role for FKN in hippocampal synaptic plasticity. FKN, on the one hand, appears to prevent excess microglial activation in the absence of injury while promoting activation of microglia and astrocytes during inflammatory episodes. Thus, FKN appears to be neuroprotective in some settings, whereas it contributes to neuronal damage in others. Many progressive neuroinflammatory disorders that are associated with increased microglial activation, such as Alzheimer's disease, show disruption of the FKN/CX3CR1 communication system. Thus, targeting CX3CR1 receptor hyperactivation with specific antagonists in such neuroinflammatory conditions may eventually lead to novel neurotherapeutics.
    Full-text · Article · Dec 2013 · Open Biology
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