Control of microglial neurotoxicity by the fractalkine receptor

• DOI: 10.1038/nn1715
• Publication Date: 2006-05-28T17:30:32Z
• Authors: Astrid E Cardona; Erik P Pioro; Margaret E Sasse; Volodymyr Kostenko; Sandra M Cardona; Ineke M Dijkstra; DeRen Huang; Grahame Kidd; Stephen Dombrowski; RanJan Dutta; Jar-Chi Lee; Donald N Cook; Steffen Jung; Sergio A Lira; Dan R Littman; Richard M Ransohoff
• Keywords: Central Nervous System; Lipopolysaccharides; Analysis of Variance; 0303 health sciences; Cell Death; Calcium-Binding Proteins; Green Fluorescent Proteins; Microfilament Proteins; CX3C Chemokine Receptor 1; Mice, Transgenic; Nerve Tissue Proteins; Flow Cytometry; Immunohistochemistry; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Animals; Cytokines; Microglia; Motor Neuron Disease; Cells, Cultured

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 Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.