Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage

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, CX(3)CR1, is predominantly expressed on microglia. This review focuses on several important functional roles for FKN/CX(3)CR1 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/CX(3)CR1 communication system. Thus, targeting CX(3)CR1 receptor hyperactivation with specific antagonists in such neuroinflammatory conditions may eventually lead to novel neurotherapeutics

Neuronal ICAM-5 Inhibits Microglia Adhesion and Phagocytosis and Promotes an Anti-inflammatory Response in LPS Stimulated Microglia

The intercellular adhesion molecule-5 (ICAM-5) regulates neurite outgrowth and synaptic maturation. ICAM-5 overexpression in the hippocampal neurons induces filopodia formation in vitro. Since microglia are known to prune supernumerous synapses during development, we characterized the regulatory effect of ICAM-5 on microglia. ICAM-5 was released as a soluble protein from N-methyl-D-aspartic acid (NMDA)-treated neurons and bound by microglia. ICAM-5 promoted down-regulation of adhesion and phagocytosis in vitro. Microglia formed large cell clusters on ICAM-5-coated surfaces whereas they adhered and spread on the related molecule ICAM-1. ICAM-5 further reduced the secretion of the proinflammatory cytokines tumor necrosis factor a (TNF-alpha) and interleukin 1 beta (IL-1 beta), but on the contrary induced the secretion of the antiinflammatory IL-10 from lipopolysaccharide (LPS) stimulated microglia. Thus, ICAM-5 might be involved in the regulation of microglia in both health and disease, playing an important neuroprotective role when the brain is under immune challenges and as a "don't-eat-me" signal when it is solubilized from active synapses.Peer reviewe

Role of Fractalkine/CX3CR1 Interaction in Light-Induced Photoreceptor Degeneration through Regulating Retinal Microglial Activation and Migration

Background: Excessive exposure to light enhances the progression and severity of some human retinal degenerative diseases. While retinal microglia are likely to be important in neuron damage associated with these diseases, the relationship between photoreceptor damage and microglial activation remains poorly understood. Some recent studies have indicated that the chemokine fractalkine is involved in the pathogenesis of many neurodegenerative diseases. The present study was performed to investigate the cross-talk between injured photoreceptors and activated retinal microglia, focusing on the role of fractalkine and its receptor CX3CR1 in light-induced photoreceptor degeneration. Methodology/Principal Findings: Both in vivo and in vitro experiments were involved in the research. In vivo, Sprague– Dawley rats were exposed to blue light for 24 hours. In vitro, the co-culture of primary retinal microglia and a photoreceptor cell line (661W cell) was exposed to blue light for five hours. Some cultures were pretreated by the addition of anti-CX3CR1 neutralizing antibody or recombinant fractalkine. Expression of fractalkine/CX3CR1 and inflammatory cytokines was detected by immunofluorescence, real-time PCR, Western immunoblot analysis, and ELISA assay. TUNEL method was used to detect cell apoptosis. In addition, chemotaxis assay was performed to evaluate the impact of soluble fractalkine on microglial migration. Our results showed that the expression of fractalkine that was significantly upregulated after exposure to light, located mainly at the photoreceptors. The extent of photoreceptor degeneration and microglial migratio

Neuronal Chemokines: Versatile Messengers In Central Nervous System Cell Interaction

Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemokines are generally found under both physiological and pathological conditions. Whereas many reports describe chemokine expression in astrocytes and microglia and their role in the migration of leukocytes into the CNS, only few studies describe chemokine expression in neurons. Nevertheless, the expression of neuronal chemokines and the corresponding chemokine receptors in CNS cells under physiological and pathological conditions indicates that neuronal chemokines contribute to CNS cell interaction. In this study, we review recent studies describing neuronal chemokine expression and discuss potential roles of neuronal chemokines in neuron–astrocyte, neuron–microglia, and neuron–neuron interaction

Defective microglial development in the hippocampus of Cx3cr1 deficient mice

Microglial cells participate in brain development and influence neuronal loss and synaptic maturation. Fractalkine is an important neuronal chemokine whose expression increases during development and that can influence microglia function via the fractalkine receptor, CX3CR1. Mice lacking Cx3cr1 show a variety of neuronal defects thought to be the result of deficient microglia function. Activation of CX3CR1 is important for the proper migration of microglia to sites of injury and into the brain during development. However, little is known about how fractalkine modulates microglial properties during development. Here we examined microglial morphology, response to ATP, and K(+) current properties in acute brain slices from Cx3cr1 knockout mice across postnatal hippocampal development. We found that fractalkine signaling is necessary for the development of several morphological and physiological features of microglia. Specifically, we found that the occurrence of an outward rectifying K(+) current, typical of activated microglia, that peaked during the second and third postnatal week, was reduced in Cx3cr1 knockout mice. Fractalkine signaling also influenced microglial morphology and ability to extend processes in response to ATP following its focal application to the slice. Our results reveal the developmental profile of several morphological and physiological properties of microglia and demonstrate that these processes are modulated by fractalkine signaling