Control of microglial neurotoxicity by the fractalkine receptor

Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor ( CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1(-/-) mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1(-/-) mice showed more extensive neuronal cell loss than Cx3cr(+) littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.