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 Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
Cardona
Astrid E
AE
Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland, Ohio 44195, USA.
Pioro
Erik P
EP
Sasse
Margaret E
ME
Kostenko
Volodymyr
V
Cardona
Sandra M
SM
Dijkstra
Ineke M
IM
Huang
Deren
D
Kidd
Grahame
G
Dombrowski
Stephen
S
Dutta
RanJan
R
Lee
Jar-Chi
JC
Cook
Donald N
DN
Jung
Steffen
S
Lira
Sergio A
SA
Littman
Dan R
DR
Ransohoff
Richard M
RM
D000704:Analysis of Variance; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects* / Q000502:physiology*; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019707:Receptors, Chemokine / Q000172:deficiency / Q000502:physiology*
C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D019707:Receptors, Chemokine; D049452:Green Fluorescent Proteins