Roles of fractalkine in neuron-microglia interaction at brain injury

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Fractalkine is a novel chemokine which has a CX3C motif and a membrane-bound form. We previously reported that, in the rat brain, fractalkine mRNA was expressed in neurons while the mRNA for its receptor (CX3CR1) was in microglia. This finding suggests that fractalkine possibly plays an important role to convey the information from neurons to microglia. To examine the role if fractalkine in neuron-microglia interaction at brain injury, we investigated the expression of fractalkine and its receptor CX3CR1 and the effect of exogenous fractalkine on neuronal cell death and microglia activation after brain ischemia. mRNA levels and fractalkine-like immunoreactivity (fractalkine-ir) were examined 6h, 1d, 3d and 7d after the start of recirculation. Fractalkine mRNA was decreased in the hippocampal CA1 pyramidal layer after ischemia. On the contrary, fractalkine-ir was increased in the CA1 pyramidal layer. Fractalkine-ir began to increase at 6h and gradually got stronger till 7d. Double staining with TUNEL revealed that 5%, 52% and 96% of fractalkine-immunopositive hippocampal pyramidal neurons were TUNEL-positive at 1d, 3d and 7d, respectively. CX3CR1 mRNA was robustly increased in the hippocampal CA1 pyramidal layer 3d and 7d after ischemia. Repetitive intracerebroventricular injections of fractalkine following ischemia increased activated microglia and exacerbated neuronal cell death in the hippocampus. These results indicate that fractalkine expressed by dying neurons possibly contributes to the activation and/or attraction of microglia and exacerbates neuronal cell death after brain ischemia.