Key Points
-
The 50 small proteins known as chemokines can be classified into four groups (α, β, γ and δ) according to the position of a pair of cysteines near their amino terminus.
-
Recent research indicates that chemokines and their receptors are important in the development of the nervous system. Their two principal functions are to direct the movement of progenitor cells to specific locations, and to ensure continued proliferation of progenitor cell populations.
-
In the embryonic cerebellum, the chemokine SDF-1 and its receptor, CXCR4, facilitate proliferation of granule cells and their migration to the internal granule layer, and are also involved in development of the dentate gyrus. MIP-1α/CCR1 chemokine signalling is probably important for the maturation of neurites and synapse formation.
-
Signalling through the chemokine Gro-α and its CXCR2 receptor directs the development of oligodendrocytes in the spinal cord. Chemokines also participate in the control of myelination in the peripheral nervous system.
-
Chemokines are widely expressed in the adult nervous system, and are up- or downregulated in response to stressful conditions and pathological stimuli. Their exact role in the adult nervous system is unknown, but data support their involvement in neuronal excitability, synaptic communication and cell survival.
-
Most chemokines are secreted from cells, and their effects are transduced through the activation of G-protein-coupled receptors. These effects can be mediated by interactions with other signalling systems, including the mitogen-activated protein kinase, Janus kinase (JAK) kinase, Sonic hedgehog, ephrin-B/Eph-B, pituitary adenylate cyclase activating protein and Slit/Robo pathways.
-
Chemokines are implicated in the manifestation of various brain disorders. They might, therefore, constitute novel therapeutic targets for the neuroinflammation associated with multiple sclerosis and Alzheimer's disease, human immunodeficiency virus 1 (HIV-1)-related cognitive, motor and sensory abnormalities, and brain neoplasias (for example, glial tumours and neuroblastomas).
Abstract
During the development of the nervous system, populations of progenitor cells that eventually become neurons and glia face the complex task of finding their way from their place of birth to their final destinations. What are the molecular processes that provide the information for guiding progenitor cells along their way? In this article, we discuss recent information indicating that chemokines and their receptors are of great importance in directing the proliferation and migration of immature neurons, glia and their precursors. Furthermore, chemokine receptor function in the nervous system continues to be important throughout adult life, and chemokines participate in various brain disorders, including AIDS dementia, neuroinflammatory disease and neuroplasia, making them important potential therapeutic targets in these cases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rossi, D. & Zlotnik, A. The biology of chemokines and their receptors. Ann. Rev. Immunol. 18, 217–242 (2000).
Ma, Q., Jones, D. & Springer, T. A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463–471 (1999).
Schwartz, G. N. & Farber, J. M. in Universes in Delicate Balance: Chemokines and the Nervous System (eds Ransohoff, R. M., Suzuki, K., Proudfoot, A. E. I., Hickey, W. F. & Harrison, J. K.) 119–128 (Elsevier, New York, 2002).
Szekanecz, Z. & Koch, A. E. Chemokines and angiogenesis. Curr. Opin. Rheumatol. 13, 202–208 (2001).
Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).
Berger, E. A., Murphy, P. M. & Farber, J. M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Ann. Rev. Immunol. 17, 657–700 (1999).
Proudfoot, A. E. I. Chemokine receptors: multifaceted therapeutic targets. Nature Rev. Immunol. 2, 106–115 (2002).
Doitsidou, M. et al. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111, 647–659 (2002).
McGrath, K. E., Koniski, A. D., Maltby, K. M., McGann, J. K. & Palis, J. Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. Dev. Biol. 213, 442–456 (1999). A detailed study on the changing pattern of SDF-1 and CXCR4 expression during the development of the mouse embryo.
Braun, M. et al. Xenopus laevis stromal cell-derived factor 1: conservation of structure and function during vertebrate development. J. Immunol. 168, 2340–2347 (2002).
Moepps, B. et al. Characterization of a Xenopus laevis CXC chemokine receptor 4: implications for hematopoietic cell development in the vertebrate embryo. Eur. J. Immunol. 30, 2924–2934 (2000).
Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998).
DeGroot, C. J. A. & Woodroofe, M. N. The role of chemokines and chemokine receptors in CNS inflammation. Prog. Brain Res. 132, 533–544 (2001).
Murphy, P. M. et al. International union of pharmacology. XXII. Nomenclature:chemokine receptors. Pharmacol. Rev. 52, 145–176 (2000).
Murphy, P. M. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev. 54, 227–229 (2002).
Proudfoot, A. E. I., Shaw, J. P., Power, C. A. & Wells, T. N. C. in Universes in Delicate Balance: Chemokines and the Nervous System (eds Ransohoff, R. M., Suzuki, K., Proudfoot, A. E. I., Hickey, W. F. & Harrison, J. K.) 65–85 (Elsevier, New York, 2002).
Jazin, E. E., Soderstrom, S., Ebendal, T. & Larhammer, D. Embryonic expression of the mRNA for the rat homologue of the fusin/CXCR4 HIV-1 co-receptor. J. Neuroimmunol. 79, 148–154 (1997).
Lavi, E. et al. CXCR4 (Fusin), a co-receptor for the type I human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. Am. J. Pathol. 151, 1035–1042 (1997).
Moepps, B., Frodl, R., Rodewald, H. R., Bagglioni, M. & Gierschik, P. Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell derived factor-1-α activation of Gi2 are differentially expressed in vivo. Eur. J. Immunol. 27, 2102–2112 (1997).
Horuk, R. et al. Expression of chemokine receptors by subsets of neurons in the central nervous system. J. Immunol. 158, 2882–2890 (1997).
Bajetto, A., Bonavia, R., Barbero, S. & Schettini, G. Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J. Neurochem. 82, 1311–1329 (2002).
Bajetto, A., Bonavia, R., Barbero, S., Florio, T. & Schettini, G. Chemokines and their receptors in the central nervous system. Front. Neuroendocrinol. 22, 147–184 (2001).
Martin-Garcia, J., Kolson, D. L. & Gozalez-Scarano, F. Chemokine receptors in the brain: their role in HIV infection and pathogenesis. AIDS 16, 1709–1730 (2002).
Meucci, O. et al. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc. Natl Acad. Sci. USA 95, 14500–14505 (1998). The first paper to demonstrate the diverse short- and long-term effects produced by chemokines on neurons.
Oh, S. B. et al. Chemokines and gp120 produce pain hypersensitivity by directly exciting polymodal nociceptors. J. Neurosci. 21, 5027–5035 (2001).
Gillard, S. E., Mastracci, R. M. & Miller, R. J. Expression of functional chemokine receptors by cerebellar neurons. J. Neuroimmunol. 124, 16–28 (2002).
Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I. & Littman, D. R. Function of chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393, 595–599 (1998).
Ma, Q. et al. Impaired B lymphopoiesis, myelopoiesis and derailed cerebellar neuronal migration in CXCR4 and SDF-1 deficient mice. Proc. Natl. Acad. Sci. USA 95, 9448–9453 (1998). References 27 and 28 were the first to demonstrate the importance of SDF-1/CXCR4 signalling in the development of the cerebellum.
Klein, R. S. et al. SDF-1α induces chemotaxis and enhances sonic hedgehog induced proliferation of cerebellar granule cells. Development 128, 1971–1981 (2001). This paper examines the mechanism of SDF-1 action on granule cells in the EGL and how SDF-1 and Shh interact to control granule cell precursor proliferation.
Reiss, K., Mentlein, R., Sievers, J. & Hartmann, D. Stromal cell derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granule layer. Neuroscience 115, 295–305 (2002).
Hartmann, D., Schulze, M. & Sievers, J. Meningeal cells stimulate and direct the migration of cerebellar external granule cells in vitro. J. Neurocytol. 27, 395–409 (1998).
Zhu, Y. et al. Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nature Neurosci. 5, 719–720 (2002).
Borghesani, P. R. et al. BDNF stimulates migration of cerebellar granule cells. Development 129, 1435–1442 (2002).
Bleul, C., Schultze, J. L. & Springer, T. A. B lymphocyte chemotaxis regulated in association with microanatomic localization, differentiation state and B cell receptor engagement. J. Exp. Med. 187, 753–762 (1998).
Cowell, R. M. & Silverstein, F. S. Developmental changes in the expression of chemokine receptor CCR1 in the rat cerebellum. J. Comp. Neurol., 457, 7-23A recent study that strongly indicates the importance of MIP1-α/CCR1 signalling in the development of the cerebellum.
Xiang, Y. et al. Nerve growth cone guidance mediated by G-protein-coupled receptors. Nature Neurosci. 5, 843–848 (2002).
Chalasani, S. H., Sabelko, K. A., Sunshine R. J., Littman D. R. & Raper J. A. A Chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and is required for normal axon path finding. J. Neurosci. 23, 1360–1371 (2003). These two papers demonstrate that SDF-1/CXCR4 signalling plays an important part in axonal guidance. CXCR4 knockout mice show a sensory neuron axon pathfinding defect.
Lu, M., Grove, E. A. & Miller, R. J. Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc. Natl Acad. Sci. 99, 7090–7095 (2002).
Bagri, A. et al. The chemokine SDF-1 regulates migration of dentate granule cells. Development 129, 4249–4260 (2002). References 37 and 38 demonstrated the importance of SDF-1/CXCR4 signalling in the normal development of the dentate gyrus.
Altman, J. & Bayer, S. A. Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J. Comp. Neurol. 301, 325–342 (1990).
Altman, J. & Bayer, S. A. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J. Comp. Neurol. 301, 365–381 (1990).
Sievers, J., Hartmann, D., Pehlemann, F. W. & Berry, M. Development of astroglial cells in the proliferative matrices, the granule cell layer and the hippocampal fissure of the hamster dentate gyrus. J. Comp Neurol. 320, 1–32 (1992).
Gould, E. & Gross, C. G. Neurogenesis in adult mammals: some progress and problems. J. Neurosci. 22, 619–23 (2002).
Hartmann, D., De Strooper, B. & Saftig, P. Presenilin-1 deficiency leads to loss of Cajal–Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr. Biol. 9, 719–727 (1999).
Bolin, L. M. et al. Primary sensory neurons migrate in response to the chemokine RANTES. J. Neuroimmunol. 81, 49–57 (1998).
Luan, J., Furuta, Y., Du, J. & Richmond, A. Developmental expression of two CXC chemokines, MIP-2 and KC, and their receptors. Cytokine 14, 253–263 (2001).
Tsai, H. H. et al. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110, 373–383 (2002). This paper demonstrates the importance of GRO-α/CXCR2 signalling in the regulation of myelination in the developing spinal cord.
Robinson, S., Tani, M., Streiter, R. M., Ransohoff, R. M. & Miller, R. H. The chemokine growth-related oncogene-α promotes spinal cord precursor proliferation. J. Neurosci. 18, 10457–10463 (1998).
Wu, Q., Miller, R. H., Ransohoff, R. M., Robinson, S., & Nishayama, A. Elevated levels of the chemokine GRO-1 correlate with elevated oligodendrocyte progenitor proliferation in the jimpy mutant. J. Neurosci. 20, 2609–2617 (2000).
Kury, P., Greiner-Petter, R., Cornely, C., Jurgens, T. & Muller, H. W. Mammalian achaete scute homolog 2 is expressed in the adult sciatic nerve and regulates the expression of Krox 24, Mob-1, CXCR4 and p57kip2 in Schwann cells. J. Neurosci. 22, 7586–7595 (2002). This paper strongly indicates a role for SDF-1/CXCR4 signalling in the control of remyelination of peripheral nerves following injury.
Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nature Rev. Mol. Cell Biol. 3, 639–650 (2002).
Miller, R. J. Presynaptic receptors Ann. Rev. Pharmacol. Toxicol. 38, 201–227 (1998).
Molina-Holgado, E. et al. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J. Neurosci. 22, 9742–9753 (2002).
Yan, G. M., Lin, S. Z., Irwin, R. P. & Paul, S. M. Activation of muscarinic cholinergic receptors blocks apoptosis of cultured cerebellar granule neurons. Mol. Pharmacol. 47, 248–257 (1995).
Vaudry, D. et al. PACAP protects cerebellar granule neurons against oxidative stress induced apoptosis. Eur. J. Neurosci. 15, 1451–1460 (2002).
Madani, N., Kozak, S. L., Kavanaugh, M. P. & Kabat, D. gp120 envelope glycoproteins of human immunodeficiency viruses competitively antagonize signaling by coreceptors CXCR4 and CCR5. Proc. Natl Acad. Sci. USA 95, 8005–8010 (1998).
Oh, S. B., Endoh, T., Simen, A. A., Ren, D. & Miller, R. J. Regulation of calcium currents by chemokines and their receptors. J. Neuroimmunol. 123, 66–75 (2002).
Ragozzino, D., Renzi, M., Giovannelli, A. & Eusebi, F. Stimulation of chemokine CXC receptor 4 induces synaptic depression of evoked parallel fibers inputs onto Purkinje neurons in mouse cerebellum. Neuroimmunol. 127, 30–36 (2002). An important demonstration of the rapid effects of chemokines on neuronal communication. An example of the control of transmitter release by presynaptic CXCR4 receptors.
Limatola, C. et al. SDF-1α-mediated modulation of synaptic transmission in rat cerebellum. Eur. J. Neurosci. 12, 2497–2504 (2000).
Ragozzino, D. et al. Modulation of the neurotransmitter release in rat cerebellar neurons by GRO-β. Neuroreport 9, 3601–3606 (1998).
Giovannelli, A. et al. CXC chemokines interleukin-8 (IL-8) and growth-related gene product-α (GRO-α) modulate Purkinje neuron activity in mouse cerebellum. J. Neuroimmunol. 92, 122–132 (1998).
Puma, C., Danik, M., Quirion, R., Ramon, F. & Williams, S. The chemokine interleukin-8 acutely reduces Ca2+ currents in identified cholinergic septal neurons expressing CXCR1 and CXCR2 receptor mRNAs. J. Neurochem. 78, 960–971 (2001).
Limatola, C. et al. The chemokine growth-related gene product-α protects rat cerebellar granule cells from apoptotic cell death through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors. Proc. Natl Acad. Sci. USA 97, 6197–6201 (2000).
Araujo, D. M. & Cotman, C. Trophic effects of interleukin-4, -7 and -8 on hippocampal neuronal cultures: potential involvement of glial-derived factors. Brain Res. 600, 49–55 (1993).
Meucci, O., Fatatis, A., Simen, A. A. & Miller, R. J. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc. Natl Acad. Sci. USA 97, 8075–8080 (2000).
Kaul, M. & Lipton, S. A. Chemokines and activated macrophages in HIV-1 and gp120-induced neuronal apoptosis. Proc. Natl Acad. Sci. USA 96, 8212–8216 (1999).
Tong, N. et al. Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J. Immunol. 164, 1333–1339 (2000).
Lazarini, F. et al. Differential signaling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur. J. Neurosci. 12, 117–125 (2000).
Xia, M. & Hyman, B. T. GROα/KC, a chemokine receptor CXCR2 ligand, can be a potent trigger for neuronal ERK1/2 and PI-3 kinase pathways and for tau hyperphosphorylation-a role in Alzheimer's disease? J. Neuroimmunol. 122, 55–64 (2002).
Xia, M. Q., Bacskai, B. J., Knowles, R. B., Qin, S. X. & Hyman, B. T. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease. J. Neuroimmunol. 108, 227–235 (2000).
Hesselgesser, J. et al. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4. Curr. Biol. 8, 595–598 (1998).
Vlahakis, S. R. et al. G-protein-coupled chemokine receptors induce both survival and apoptotic signaling pathways. J. Immunol. 169, 5546–5554 (2002).
Hatori, K., Nagai, A., Heisel, R., Ryu, J. K. & Kim, S. U. Fractalkine and fractalkine receptors in human neurons and glial cells. J. Neurosci. Res. 69, 418–426 (2002).
Schreiber, R. C. et al. Monocyte chemoattractant protein (MCP)-1 is rapidly expressed by sympathetic ganglion neurons following axonal injury. Neuroreport 12, 601–606 (2001).
Stumm, R. K. et al. A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform selective regulation of SDF-1 expression modulates CXCR4 dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia J. Neurosci. 22, 5865–5878 (2002). The most complete description so far of the distribution of SDF-1 and CXCR4 in the adult brain and changes in their expression in response to stroke.
Banisadr, G. et al. Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in cholinergic and dopaminergic neurons. Eur. J. Neurosci. 16, 1661–1671 (2002).
Banisadr, G. et al. Characterization and visualization of [125I]-stromal cell derived factor 1α binding to the CXCR4 receptors in rat brain and human neuroblastoma cells. J. Neuroimmunol. 110, 151–160 (2000).
Gleichmann, M. et al. Cloning and characterization of SDF-1γ, a novel SDF-1 chemokine transcript with developmentally regulated expression in the nervous system. Eur. J. Neurosci. 12, 1857–1866 (2000).
Tham, T. N. et al. Developmental pattern of expression of the α-chemokine stromal cell derived factor 1 in the rat central nervous system. Eur. J. Neurosci. 13, 845–856 (2001).
Cheng, Z. J. et al. β-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between β-arrestin and CXCR4. J. Biol. Chem. 275, 2479–2485 (2000).
Perry, S. J. & Lefkowitz, R. J. Arresting developments in heptahelical receptor signaling and regulation. Trends Cell Biol. 12, 130–138 (2002).
Meng, S. Z., Oka, A. & Takashima, S. Development expression of monocyte chemoattractant protein-1 in the human cerebellum and brainstem. Brain Dev. 21, 30–35 (1999).
Van der Meer, P., Ulrich, A. M., Gonzalez-Scarano, F. & Lavi, E. Immunohistochemical analysis of CCR2, CCR3, CCR5 and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp. Mol. Pathol. 69, 192–201 (2000).
Westmoreland, S. V. et al. Developmental expression of CCR5 and CXCR4 in the rhesus macaque brain. J. Neuroimmunol. 122, 146–158 (2002).
Rodriguez-Frade, J. M., Mellado, M. & Martinez, A. C. Chemokine receptor dimerization: two are better than one. Trends Immunol. 22, 612–617 (2001).
Issafras, H. et al. Constitutive agonist-independent CCR5 oligomerization and antibody-mediated clustering occurring at physiological levels of receptors. J. Biol. Chem. 277, 34666–34673 (2002).
Babcock, G. J., Farzan, M. & Sodroski, J. Ligand-independent dimerization of CXCR4, a principal HIV-1 coreceptor. J. Biol. Chem., 278, 3378-3385 (2003).
Zhang, X. F., Wang, J. F., Matczak, E., Proper, J. A. & Groopman, J. E. Janus kinase 2 is involved in stromal cell-derived factor-1α-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells. Blood 97, 3342–3348 (2001).
Lu, Q., Sun, E. E., Klein, R. S. & Flanagan, J. G. Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G-protein-coupled chemoattraction. Cell 105, 69–79 (2001). This paper describes how activation of reverse signalling by ephrin-b might influence CXCR4 signalling through the recruitment of a new RGS protein that binds ephrin-b through a PDZ domain.
Nicot, A., Lelievre, V., Tam, J., Waschek, J. A. & DiCicco-Bloom, E. Pituitary adenylate cyclase activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation. J. Neurosci. 22, 9244–9254 (2002).
Lee, F. S., Rajagopal, R., Kim, A. H., Chang, P. C. & Chao, M. V. Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J. Biol. Chem. 277, 9096–9102 (2002).
Borghesani, P. R. et al. BDNF stimulates migration of cerebellar granule cells. Development 129, 1435–1442 (2002).
Brose, K. & Tessier-Lavigne, M. Slit proteins: key regulators of axon guidance, axonal branching and cell migration. Curr. Opin. Neurobiol. 10, 95–102 (2000).
Wu, J. Y. et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410, 948–952 (2001).
Gerard, C. & Rollins, B. J. Chemokines and disease. Nature Immunol. 2, 108–115 (2001).
Ransohoff, R. M. The chemokine system in neuroinflammation: an update. J. Infect. Dis. (Suppl.) 186, S152–S156 (2002).
Tanabe, S. et al. Murine astrocytes express a functional chemokine receptor. J. Neurosci. 17, 6522–6528 (1997).
Dorf, M. E., Berman, M. A., Tanabe, S., Heesen, M. & Luo, Y. Astrocytes express functional chemokine receptors. J. Neuroimmunol. 111, 109–121 (2000).
Andejelkovic, A. V., Song, L., Dzenko, K. A., Cong, H. & Pachter, J. S. Functional expression of CCR2 by human fetal astrocytes. J. Neurosci. Res. 70, 219–231 (2002).
Bajetto, A. et al. Stromal cell derived factor 1-α induces astrocyte proliferation through the activation of extracellular signal regulated kinases 1 and 2 pathway. J. Neurochem. 77, 1226–1236 (2001).
Rezaie, P., Trillo-Pazos, G., Everall, I. P. & Male, D. K. Expression of β-chemokine and chemokine receptors in human fetal astrocyte and microglial cultures: potential role of chemokines in the developing CNS. Glia 37, 64–75 (2002).
Heesen, M. et al. Mouse astrocytes respond to the chemokines MCP-1 and KC, but reverse transcriptase-polymerase chain reaction does not detect mRNA for the KC or new MCP-1 receptor. J. Neurosci. Res. 45, 382–391 (1996).
Dorf, M. E., Fischer, F. R., Berman, M. A. & Luo, Y. Universes in Delicate Balance: Chemokines and the Nervous System (eds Ransohoff, R. M., Suzuki, K., Proudfoot, A. E. I., Hickey, W. F. & Harrison, J. K.) 257–272 (Elsevier, New York, 2002).
Odemis, V., Moepps, B., Gierschik, P. & Engele, J. Interleukin-6 and cAMP induce stromal cell derived factor 1 chemotaxis in astroglia by up-regulating CXCR4 cell surface expression. J. Biol. Chem. 277, 39801–39808 (2002).
Luo, Y. et al. RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes. Glia 39, 19–30 (2002). This paper provides a good example of how astrocytes can potentially mediate the production of chemokines as part of the neuroinflammatory process.
Johnstone, M., Gearing, A. J. & Miller, K. M. A central role for astrocytes in the inflammatory response to β-amyloid; chemokines, cytokines and reactive oxygen species are produced. J. Neuroimmunol. 93, 182–193 (1999).
Kaul, M., Garden, G. A. & Lipton, S. A. Pathways to neuronal injury and apoptosis in HIV associated dementia. Nature 410, 988–994 (2001).
Gabuzda, D. & Wang, J. Chemokine receptors and mechanisms of cell death in HIV neuropathogenesis. J. Neurovirol. 6 (Suppl. 1), S24–32 (2000).
Kolson, D. L. & Gonzalez-Scarano, F. HIV-associated neuropathies: role of HIV-1, CMV, and other viruses. J. Peripher. Nerv. Syst. 6, 2–7 (2001).
Toggas, S. M. et al. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367, 188–193 (1994).
Meucci, O. & Miller, R. J. gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-β1. J. Neurosci. 16, 4080–4088 (1996).
Corasaniti, M. T. et al. Exploitation of the HIV-1 coat glycoprotein, gp120, in neurodegenerative studies in vivo. J. Neurochem. 79, 1–8 (2001).
Gorry, P. R. et al. Macrophage tropism of human immunodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity. J. Virol. 75, 10073–10089 (2001).
Davis, C. B. et al. Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5. J. Exp. Med. 186, 1793–1798 (1997).
Bodner, A. et al. Mixed lineage kinase 3 mediates gp120IIIB-induced neurotoxicity. J. Neurochem. 82, 1424–1434 (2002).
Bezzi, P. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nature Neurosci. 4, 702–710 (2001). This paper demonstrates how CXCR4 receptors on astrocytes might contribute to the death of neurons through the gp120 induced release of glutamate.
Vesce, S., Bezzi, P., Rossi, D., Meldolesi, J. & Volterra, A. HIV-1 gp120 glycoprotein affects the astrocyte control of extracellular glutamate by both inhibiting the uptake and stimulating the release of the amino acid. FEBS Lett. 411, 107–109 (1997).
Sehgal, A., Keener, C., Boynton, A. L., Warrick, J. & Murphy, G. P. CXCR4, a chemokine receptor, is over expressed and required for proliferation of glioblastoma tumor cells. J. Surg. Oncol. 69, 99–104 (1998).
Zhou, Y., Larsen, P. H., Hao, C. & Yong, V. W. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J. Biol. Chem. 277, 49481–49487 (2002).
Oh, J. W. et al. CXC chemokine receptor 4 expression and function in human astroglial cells. J. Immunol. 166, 2695–2704 (2001).
Rempel, S. A., Dudas, S., Ge, S. & Gutierrez, J. A. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin. Cancer. Res. 6, 102–111 (2000).
Kielian, T., Van Rooijen, N. & Hickey, W. F. MCP-1 expression in CNS-1 astrocytoma cells: implications for macrophage infiltration into tumors in vivo. J. Neurooncol. 56, 1–12 (2002).
Choi, C. et al. Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Cancer Res. 61, 3084–3091 (2001).
Bajetto, A. et al. Glial and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal cell derived factor-1. J. Neurochem. 73, 2348–2357 (1999).
Catani, M. V. et al. gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors. J. Neurochem. 74, 2373–2379 (2000).
Geminder, H. et al. A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J. Immunol. 167, 4747–4757 (2001).
Author information
Authors and Affiliations
Corresponding author
Glossary
- MUCIN
-
A highly glycosylated protein that is rich in serine or threonine for O-glycosylation.
- TROPISM
-
The range of cells that can be productively infected by a virus.
- MITOGEN
-
An agent that induces mitosis.
- HILUS
-
A subdivision of the hippocampus that is rich in interneurons. It is located between the CA3 region and the dentate gyrus.
- CAJAL–RETZIUS CELL
-
A transient pioneer neuron that is located in layer I of the developing neocortex and hippocampus.
- LISSENCEPHALIC DISEASE
-
A congenital lack or underdevelopment of the convolutional pattern of the cerebral cortex, owing to a defect of development.
- WALLERIAN DEGENERATION
-
A form of degeneration occurring in nerve fibres as a result of their division. Named after A. V. Waller, who published an account of it in 1850.
- HELIX–LOOP–HELIX
-
A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop.
- PARACRINE
-
Signalling process that involves the secretion from a cell of molecules, which act on other cells in the immediate vicinity that express appropriate receptors, rather than acting on the same cell (autocrine signalling) or on remote cells (endocrine signalling).
- SCAFFOLDING PROTEINS
-
Proteins that act as scaffolds for organizing different members of a signal transduction pathway.
- NOCICEPTORS
-
Peripheral nerves, organs or mechanisms for the reception and transmission of painful or injurious stimuli.
- PERTUSSIS TOXIN
-
The causative agent of whooping cough, pertussis toxin causes the persistent inhibition of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.
- PDZ DOMAIN
-
A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).
- MULTIPLE SCLEROSIS
-
A neurodegenerative disorder characterized by demyelination of central nervous system tracts. Symptoms depend on the site of demyelination and include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.
- MYELIN PALLOR
-
A manifestation of the destruction of myelinated axons.
- ALLODYNIA
-
The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful. As with hyperalgaesia, this term was derived from observations of humans in which verbal reporting was used to assess pain sensitivity, and so it is difficult to designate a change in pain sensitivity in animals as allodynic or hyperalgaesic.
- GLIOMAS
-
Neuroectodermal tumours of neuroglial origin: include astrocytoma, oligodendroglioma and ependymoma derived from astrocytes, oligodendrocytes and ependymal cells, respectively. All infiltrate the adjacent brain tissue, but they do not metastasise.
- AUTOCRINE
-
An agent that acts on the cell that produced it.
- NEUROBLASTOMAS
-
Malignant tumours derived from primitive ganglion cells. Mainly a tumour of childhood. Most common sites are adrenal medulla and retroperitoneal tissue. The cells might partially differentiate into cells having the appearance of immature neurons.
Rights and permissions
About this article
Cite this article
Tran, P., Miller, R. Chemokine receptors: signposts to brain development and disease. Nat Rev Neurosci 4, 444–455 (2003). https://doi.org/10.1038/nrn1116
Issue Date:
DOI: https://doi.org/10.1038/nrn1116