Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival.
Recent in vitro and in vivo studies have shown that the chemokine fractalkine is widely expressed in the brain and localized principally to neurons. Central nervous system expression of CX(3)CR1, the only known receptor for fractalkine, has been demonstrated exclusively on microglia and astrocytes. Thus, it has been proposed that fractalkine regulates cellular communication between neurons (that produce fractalkine) and microglia (that express its receptor). Here we show, for the first time, that hippocampal neurons also express CX(3)CR1. Receptor activation by soluble fractalkine induces activation of the protein kinase Akt, a major component of prosurvival signaling pathways, and nuclear translocation of NF-kappaB, a downstream effector of Akt. Fractalkine protects hippocampal neurons from the neurotoxicity induced by the HIV-1 envelope protein gp120(IIIB), an effect blocked by anti-CX(3)CR1 antibodies. Experiments with two different inhibitors of the phosphatidylinositol 3-kinase, a key enzyme in the activation of Akt, and with a phospholipid activator of Akt demonstrate that Akt activation is responsible for the neuroprotective effects of fractalkine. These data show that neuronal CX(3)CR1 receptors mediate the neurotrophic effects of fractalkine, suggesting that fractalkine and its receptor are involved in a complex network of both paracrine and autocrine interactions between neurons and glia.
Meucci
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O
Department of Neurobiology, Pharmacology, and Physiology, and Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA.
Fatatis
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Simen
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Miller
R J
RJ
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D000073883:CX3C Chemokine Receptor 1; D002470:Cell Survival; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC / Q000378:metabolism*; D046508:Culture Techniques / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D020672:I-kappa B Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D011994:Recombinant Proteins; C515540:Cx3cl1 protein, rat; C000606206:Nfkbia protein, rat; C494920:Akt1 protein, rat