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.

[1]  L. Pfeffer,et al.  NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase , 1999, Nature.

[2]  J. Romashkova,et al.  NF-κB is a target of AKT in anti-apoptotic PDGF signalling , 1999, Nature.

[3]  S. Korsmeyer,et al.  Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis , 1999, Nature.

[4]  R. Maki,et al.  Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia. , 1999, Journal of immunology.

[5]  K. Bacon,et al.  Activation of mitogen-activated protein kinase regulates eotaxin-induced eosinophil migration. , 1999, Journal of immunology.

[6]  M. Peter,et al.  Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. , 1998, Current opinion in immunology.

[7]  W. Streit,et al.  Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Xiaodong Wang,et al.  Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors , 1998, Cell.

[9]  D. Ferrari,et al.  Oxidative stress and hypoxia/reoxygenation trigger CD95 (APO‐1/Fas) ligand expression in microglial cells , 1998, FEBS letters.

[10]  C. Raine,et al.  Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. , 1997, Journal of immunology.

[11]  T. Schall,et al.  Identification and Molecular Characterization of Fractalkine Receptor CX3CR1, which Mediates Both Leukocyte Migration and Adhesion , 1997, Cell.

[12]  L. Peso,et al.  Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. , 1997, Science.

[13]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[14]  V. Kuchroo,et al.  Fas- and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis. , 1997, Journal of immunology.

[15]  A. Cross,et al.  Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system. , 1997, Journal of immunology.

[16]  C. Raine,et al.  Multiple sclerosis: Oligodendrocytes display cell death–related molecules in situ but do not undergo apoptosis , 1997, Annals of neurology.

[17]  J. Gutiérrez-Ramos,et al.  Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation , 1997, Nature.

[18]  Wei Wang,et al.  A new class of membrane-bound chemokine with a CX3C motif , 1997, Nature.

[19]  G. Evan,et al.  Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB , 1997, Nature.

[20]  J. Sodroski,et al.  CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia , 1997, Nature.

[21]  J. Antel,et al.  Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death , 1996, The Journal of experimental medicine.

[22]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[23]  J. Menonna,et al.  Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain , 1996, The Journal of experimental medicine.

[24]  M. Lenardo.  Fas and the art of lymphocyte maintenance , 1996, The Journal of experimental medicine.

[25]  Masanori Kato,et al.  Fas antigen expression in brains of patients with Alzheimer-type dementia , 1995, Brain Research.

[26]  M. Lenardo,et al.  Induction of apoptosis in mature T cells by tumour necrosis factor , 1995, Nature.

[27]  C. Combadière,et al.  Cloning, chromosomal localization, and RNA expression of a human beta chemokine receptor-like gene. , 1995, DNA and cell biology.

[28]  G. Kreutzberg,et al.  Microglia: Intrinsic immuneffector cell of the brain , 1995, Brain Research Reviews.

[29]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[30]  Z. Oltvai,et al.  Checkpoints of dueling dimers foil death wishes , 1994, Cell.

[31]  Yoshihiro Yamamoto,et al.  Fas antigen mRNA induction in postischemic murine brain , 1994, Brain Research.

[32]  J. Harrison,et al.  cDNA cloning of a G-protein-coupled receptor expressed in rat spinal cord and brain related to chemokine receptors , 1994, Neuroscience Letters.

[33]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[34]  M. Lenardo,et al.  Ligand-induced apoptosis of mature T lymphocytes (propriocidal regulation) occurs at distinct stages of the cell cycle. , 1993, Leukemia.

[35]  M. Lenardo,et al.  Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle , 1993, European journal of immunology.

[36]  F.,et al.  A Specific Inhibitor of Phosphatidylinositol 3=Kinase, , 2001 .

[37]  R. Siegel,et al.  Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment. , 1999, Annual review of immunology.

[38]  B Dewald,et al.  Human chemokines: an update. , 1997, Annual review of immunology.