The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia.
Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.
Boehme
S A
SA
Neurocrine Biosciences, Inc., San Diego, CA 92121, USA. sboehme@neurocrine.com
Lio
F M
FM
Maciejewski-Lenoir
D
D
Bacon
K B
KB
Conlon
P J
PJ
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001921:Brain / Q000166:cytology* / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC / Q000502:physiology*; D004789:Enzyme Activation / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology*; D017628:Microglia / Q000166:cytology* / Q000276:immunology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051025:bcl-Associated Death Protein; D019014:fas Receptor / Q000502:physiology*
C494821:Bad protein, rat; D002352:Carrier Proteins; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; C515540:Cx3cl1 protein, rat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt