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

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

Tumor necrosis factor-alpha and interleukin-1 alpha enhance glucose utilization by astrocytes: involvement of phospholipase A2

Cytokines can be produced within the nervous system by various cell types, including astrocytes, which secrete them in response to pathological processes such as viral infections. Astrocytes are known to play an important role in the homeostasis of the nervous system, in particular, by contributing to the regulation of local energy metabolism. We report that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) markedly stimulate glucose uptake and phosphorylation in primary cultures of neonatal murine astrocytes, as determined with [3H]-2-deoxyglucose ([3H]2DG). This effect is both concentration dependent, with observed EC50 values of 8 ng/ml for TNF-alpha and 30 pg/ml for IL-1 alpha, and time dependent, with a maximal response observed 24 hr after cytokine application. The effects of TNF-alpha and IL-1 alpha on glucose uptake and phosphorylation appear to be mediated by the phospholipase A2 signal transduction pathway. Evidence in support of this includes (i) inhibition by mepacrine, a phospholipase A2 inhibitor, of [3H]2DG uptake evoked by TNF-alpha and IL-1 alpha, and (ii) stimulation of [3H]arachidonic acid release by TNF-alpha and IL-1 alpha. Protein kinase C activation does not appear to be involved as the specific protein kinase C inhibitor Ro 31-7549 does not abolish TNF-alpha- or IL-1 alpha-induced increase in [3H]2DG uptake and phosphorylation. The additional glucose imported by astrocytes on exposure to TNF-alpha and IL-1 alpha is neither stored as glycogen nor released as glycolytically derived lactate, suggesting that it is processed through the tricarboxylic acid cycle or pentose phosphate pathway. These results demonstrate that TNF-alpha and IL-1 alpha can fundamentally perturb the energy metabolism of astrocytes, possibly impairing their ability to provide adequate energy substrates for neurons