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Microglia and neuronal cell death

  • José L. Marín-Teva (a1), Miguel A. Cuadros (a1), David Martín-Oliva (a1) and Julio Navascués (a1)

Microglia, the brain's innate immune cell type, are cells of mesodermal origin that populate the central nervous system (CNS) during development. Undifferentiated microglia, also called ameboid microglia, have the ability to proliferate, phagocytose apoptotic cells and migrate long distances toward their final destinations throughout all CNS regions, where they acquire a mature ramified morphological phenotype. Recent studies indicate that ameboid microglial cells not only have a scavenger role during development but can also promote the death of some neuronal populations. In the mature CNS, adult microglia have highly motile processes to scan their territorial domains, and they display a panoply of effects on neurons that range from sustaining their survival and differentiation contributing to their elimination. Hence, the fine tuning of these effects results in protection of the nervous tissue, whereas perturbations in the microglial response, such as the exacerbation of microglial activation or lack of microglial response, generate adverse situations for the organization and function of the CNS. This review discusses some aspects of the relationship between microglial cells and neuronal death/survival both during normal development and during the response to injury in adulthood.

Corresponding author
Correspondence should be addressed to: José L. Marín-Teva, Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain phone: +34-958-246335; +34-958-243258 email:
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Aarum, J., Sandberg, K., Haeberlein, S.L. and Persson, M.A. (2003) Migration and differentiation of neural precursor cells can be directed by microglia. Proceedings of the National Academy of Sciences of the U.S.A. 100, 1598315988.
Acarin, L., Gonzalez, B., Castellano, B. and Castro, A.J. (1996) Microglial response to N-methyl-D-aspartate-mediated excitotoxicity in the immature rat brain. Journal of Comparative Neurology 367, 361374.
Alliot, F., Godin, I. and Pessac, B. (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Developmental Brain Research 117, 145152.
Andjelkovic, A.V., Nikolic, B., Pachter, J.S. and Zecevic, N. (1998) Macrophages/microglial cells in human central nervous system during development: an immunohistochemical study. Brain Research 814, 1325.
Ashwell, K. (1990) Microglia and cell death in the developing mouse cerebellum. Developmental Brain Research 55, 219230.
Ashwell, K. (1991) The distribution of microglia and cell death in the fetal rat forebrain. Developmental Brain Research 58, 112.
Ashwell, K.W., Hollander, H., Streit, W. and Stone, J. (1989) The appearance and distribution of microglia in the developing retina of the rat. Visual Neuroscience 2, 437448.
Barde, Y.A. (1989) Trophic factors and neuronal survival. Neuron 2, 15251534.
Batchelor, P.E., Liberatore, G.T., Wong, J.Y., Porritt, M.J., Frerichs, F., Donnan, G.A. et al. (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Journal of Neuroscience 19, 17081716.
Bessis, A., Bechade, C., Bernard, D. and Roumier, A. (2007) Microglial control of neuronal death and synaptic properties. Glia 55, 233238.
Bianchi, M.E. (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. Journal of Leukocyte Biology 81, 15.
Biber, K., Neumann, H., Inoue, K. and Boddeke, H.W. (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends in Neurosciences 30, 596602.
Bjelobaba, I., Parabucki, A., Lavrnja, I., Stojkov, D., Dacic, S., Pekovic, S. et al. (2011) Dynamic changes in the expression pattern of ecto-5′-nucleotidase in the rat model of cortical stab injury. Journal of Neuroscience Research 89, 862873.
Block, M.L. and Hong, J.S. (2007) Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochemical Society Transactions 35, 11271132.
Block, M.L., Zecca, L. and Hong, J.S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8, 5769.
Braun, N., Lenz, C., Gillardon, F., Zimmermann, M. and Zimmermann, H. (1997) Focal cerebral ischemia enhances glial expression of ecto-5′-nucleotidase. Brain Research 766, 213226.
Braun, N., Sevigny, J., Robson, S.C., Enjyoji, K., Guckelberger, O., Hammer, K. et al. (2000) Assignment of ecto-nucleoside triphosphate diphosphohydrolase-1/cd39 expression to microglia and vasculature of the brain. European Journal of Neuroscience 12, 43574366.
Braun, N., Zhu, Y., Krieglstein, J., Culmsee, C. and Zimmermann, H. (1998) Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. Journal of Neuroscience 18, 48914900.
Brown, G.C. (2010) Nitric oxide and neuronal death. Nitric Oxide 23, 153165.
Brown, G.C. and Neher, J.J. (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Molecular Neurobiology 41, 242247.
Buss, R.R., Sun, W. and Oppenheim, R.W. (2006) Adaptive roles of programmed cell death during nervous system development. Annual Reviews of Neuroscience 29, 135.
Calderó, J., Brunet, N., Ciutat, D., Hereu, M. and Esquerda, J.E. (2009) Development of microglia in the chick embryo spinal cord: implications in the regulation of motoneuronal survival and death. Journal of Neuroscience Research 87, 24472466.
Cameron, B. and Landreth, G.E. (2010) Inflammation, microglia, and Alzheimer's disease. Neurobiology of Disease 37, 503509.
Chan, W.Y., Kohsaka, S. and Rezaie, P. (2007) The origin and cell lineage of microglia: new concepts. Brain Research Reviews 53, 344354.
Chanock, S.J., el Benna, J., Smith, R.M. and Babior, B.M. (1994) The respiratory burst oxidase. Journal of Biological Chemistry 269, 2451924522.
Chao, C.C., Hu, S., Molitor, T.W., Shaskan, E.G. and Peterson, P.K. (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. Journal of Immunology 149, 27362741.
Colton, C.A. (2009) Heterogeneity of microglial activation in the innate immune response in the brain. Journal of Neuroimmune Pharmacology 4, 399418.
Combs, C.K., Karlo, J.C., Kao, S.C. and Landreth, G.E. (2001) β-amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. Journal of Neuroscience 21, 11791188.
Conductier, G., Blondeau, N., Guyon, A., Nahon, J.L. and Rovere, C. (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. Journal of Neuroimmunology 224, 93100.
Cuadros, M.A., Coltey, P., Carmen Nieto, M. and Martin, C. (1992) Demonstration of a phagocytic cell system belonging to the hemopoietic lineage and originating from the yolk sac in the early avian embryo. Development 115, 157168.
Cuadros, M.A., García-Martín, M., Martin, C. and Ríos, A. (1991) Haemopoietic phagocytes in the early differentiating avian retina. Journal of Anatomy 177, 145158.
Cuadros, M.A., Martin, C., Coltey, P., Almendros, A. and Navascués, J. (1993) First appearance, distribution, and origin of macrophages in the early development of the avian central nervous system. Journal of Comparative Neurology 330, 113129.
Cuadros, M.A. and Navascués, J. (1998) The origin and differentiation of microglial cells during development. Progress in Neurobiology 56, 173189.
Cuadros, M.A. and Navascués, J. (2001) Early origin and colonization of the developing central nervous system by microglial precursors. Progress in Brain Research 132, 5159.
Cunha, R.A. (2005) Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade. Purinergic Signalling 1, 111134.
Dalmau, I., Vela, J.M., Gonzalez, B. and Castellano, B. (1998) Expression of purine metabolism-related enzymes by microglial cells in the developing rat brain. Journal of Comparative Neurology 398, 333346.
Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S. et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8, 752758.
David, S. and Kroner, A. (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nature Reviews Neuroscience 12, 388399.
de la Rosa, E.J. and de Pablo, F. (2000) Cell death in early neural development: beyond the neurotrophic theory. Trends in Neurosciences 23, 454458.
De Simone, R., Ajmone-Cat, M.A. and Minghetti, L. (2004) Atypical antiinflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine-phosphatidylserine receptor interaction. Molecular Neurobiology 29, 197212.
del Rio-Hortega, P. (1932) Microglia. InPenfield, W. (ed.) Cytology and Cellular Pathology of the Nervous System, vol. 2. Hafner, New York, pp. 483534.
D'Mello, C., Le, T. and Swain, M.G. (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. Journal of Neuroscience 29, 20892102.
Egensperger, R., Maslim, J., Bisti, S., Hollander, H. and Stone, J. (1996) Fate of DNA from retinal cells dying during development: uptake by microglia and macroglia (Muller cells). Developmental Brain Research 97, 18.
Elkabes, S., DiCicco-Bloom, E.M. and Black, I.B. (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. Journal of Neuroscience 16, 25082521.
Elliott, M.R., Chekeni, F.B., Trampont, P.C., Lazarowski, E.R., Kadl, A., Walk, S.F. et al. (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282286.
Fadok, V.A., Bratton, D.L., Rose, D.M., Pearson, A., Ezekewitz, R.A. and Henson, P.M. (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 8590.
Farber, K., Markworth, S., Pannasch, U., Nolte, C., Prinz, V., Kronenberg, G. et al. (2008) The ectonucleotidase cd39/ENTPDase1 modulates purinergic-mediated microglial migration. Glia 56, 331341.
Ferrer, I., Bernet, E., Soriano, E., del Rio, T. and Fonseca, M. (1990) Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes. Neuroscience 39, 451458.
Fiske, B.K. and Brunjes, P.C. (2000) Microglial activation in the developing rat olfactory bulb. Neuroscience 96, 807815.
Fitzner, D., Schnaars, M., van Rossum, D., Krishnamoorthy, G., Dibaj, P., Bakhti, M. et al. (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. Journal of Cell Science 124, 447458.
Flavin, M.P., Zhao, G. and Ho, L.T. (2000) Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro. Glia 29, 347354.
Frade, J.M. and Barde, Y.A. (1998) Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 3541.
Fukui, O., Kinugasa, Y., Fukuda, A., Fukuda, H., Tskitishvili, E., Hayashi, S. et al. (2006) Post-ischemic hypothermia reduced IL-18 expression and suppressed microglial activation in the immature brain. Brain Research 1121, 3545.
Gandelman, M., Peluffo, H., Beckman, J.S., Cassina, P. and Barbeito, L. (2010) Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis. Journal of Neuroinflammation 7, 33.
Gao, H.M., Zhou, H., Zhang, F., Wilson, B.C., Kam, W. and Hong, J.S. (2011) HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. Journal of Neuroscience 31, 10811092.
García-Porrero, J.A. and Ojeda, J.L. (1979) Cell death and phagocytosis in the neuroepithelium of the developing retina. A TEM and SEM study. Experientia 35, 375376.
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S. et al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841845.
Gordon, S. and Taylor, P.R. (2005) Monocyte and macrophage heterogeneity. Nature Reviews Immunology 5, 953964.
Graeber, M.B., Lopez-Redondo, F., Ikoma, E., Ishikawa, M., Imai, Y., Nakajima, K. et al. (1998) The microglia/macrophage response in the neonatal rat facial nucleus following axotomy. Brain Research 813, 241253.
Hanisch, U.K. (2002) Microglia as a source and target of cytokines. Glia 40, 140155.
Hanisch, U.K. and Kettenmann, H. (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10, 13871394.
Hao, A.J., Dheen, S.T. and Ling, E.A. (2001) Response of amoeboid microglia/brain macrophages in fetal rat brain exposed to a teratogen. Journal of Neuroscience Research 64, 7993.
Haynes, S.E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M.E., Gan, W.B. et al. (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nature Neuroscience 9, 15121519.
Henry, C.J., Huang, Y., Wynne, A.M. and Godbout, J.P. (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines. Brain Behavior and Immunity 23, 309317.
Herbomel, P., Thisse, B. and Thisse, C. (1999) Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126, 37353745.
Herbomel, P., Thisse, B. and Thisse, C. (2001) Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Developmental Biology 238, 274288.
Hoeppner, D.J., Hengartner, M.O. and Schnabel, R. (2001) Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202206.
Hristova, M., Cuthill, D., Zbarsky, V., Acosta-Saltos, A., Wallace, A., Blight, K. et al. (2010) Activation and deactivation of periventricular white matter phagocytes during postnatal mouse development. Glia 58, 1128.
Hsieh, C.L., Koike, M., Spusta, S.C., Niemi, E.C., Yenari, M., Nakamura, M.C. et al. (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. Journal of Neurochemistry 109, 11441156.
Hume, D.A., Perry, V.H. and Gordon, S. (1983) Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers. Journal of Cell Biology 97, 253257.
Hur, J., Lee, P., Kim, M.J., Kim, Y. and Cho, Y.W. (2010) Ischemia-activated microglia induces neuronal injury via activation of gp91phox NADPH oxidase. Biochemical and Biophysical Research Communications 391, 15261530.
Hurley, S.D., Walter, S.A., Semple-Rowland, S.L. and Streit, W.J. (1999) Cytokine transcripts expressed by microglia in vitro are not expressed by ameboid microglia of the developing rat central nervous system. Glia 25, 304309.
Ilieva, H., Polymenidou, M. and Cleveland, D.W. (2009) Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. Journal of Cell Biology 187, 761772.
Imai, F., Suzuki, H., Oda, J., Ninomiya, T., Ono, K., Sano, H. et al. (2007) Neuroprotective effect of exogenous microglia in global brain ischemia. Journal of Cerebral Blood Flow and Metabolism 27, 488500.
Jung, S., Aliberti, J., Graemmel, P., Sunshine, M.J., Kreutzberg, G.W., Sher, A. et al. (2000) Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Molecular and Cellular Biology 20, 41064114.
Kálmán, M. (1989) Dead cells can be phagocytosed by any neighboring cell in early developing rat brain. International Journal of Neuroscience 46, 139145.
Kawahara, K., Yoshida, A., Koga, K., Yokoo, S., Kuniyasu, A., Gotoh, T. et al. (2009) Marked induction of inducible nitric oxide synthase and tumor necrosis factor-alpha in rat CD40+ microglia by comparison to CD40- microglia. Journal of Neuroimmunology 208, 7079.
Kettenmann, H., Hanisch, U.K., Noda, M. and Verkhratsky, A. (2011) Physiology of microglia. Physiological Reviews 91, 461553.
Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K., Shinozaki, Y., Ohsawa, K., Tsuda, M. et al. (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 10911095.
Konduru, N.V., Tyurina, Y.Y., Feng, W., Basova, L.V., Belikova, N.A., Bayir, H. et al. (2009) Phosphatidylserine targets single-walled carbon nanotubes to professional phagocytes in vitro and in vivo. PLoS ONE 4, e4398.
Kono, H. and Rock, K.L. (2008) How dying cells alert the immune system to danger. Nature Reviews Immunology 8, 279289.
Kreutzberg, G. W. (1996) Microglia: a sensor for pathological events in the CNS. Trends in Neurosciences 19, 312318.
Kuan, C.Y., Roth, K.A., Flavell, R.A. and Rakic, P. (2000) Mechanisms of programmed cell death in the developing brain. Trends in Neurosciences 23, 291297.
Kumar, H., Kawai, T. and Akira, S. (2011) Pathogen recognition by the innate immune system. International Reviews of Immunology 30, 1634.
Lai, A.Y. and Todd, K.G. (2008) Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury. Glia 56, 259270.
Lalancette-Hebert, M., Gowing, G., Simard, A., Weng, Y.C. and Kriz, J. (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. Journal of Neuroscience 27, 25962605.
Lauber, K., Blumenthal, S.G., Waibel, M. and Wesselborg, S. (2004) Clearance of apoptotic cells: getting rid of the corpses. Molecular Cell 14, 277287.
Lauber, K., Bohn, E., Krober, S.M., Xiao, Y.J., Blumenthal, S.G., Lindemann, R.K. et al. (2003) Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717730.
Lehnardt, S. (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58, 253263.
Liang, K.J., Lee, J.E., Wang, Y.D., Ma, W., Fontainhas, A.M., Fariss, R.N. et al. (2009) Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. Investigative Ophthalmology and Visual Science 50, 44444451.
Lichanska, A.M. and Hume, D.A. (2000) Origins and functions of phagocytes in the embryo. Experimental Hematology 28, 601611.
Liu, M. and Bing, G. (2011) Lipopolysaccharide animal models for Parkinson's disease. Parkinson's Disease 2011, 327089, doi: 10.4061/2011/327089.
Liu, Z.G., Hsu, H., Goeddel, D.V. and Karin, M. (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565576.
Loane, D.J. and Byrnes, K.R. (2010) Role of microglia in neurotrauma. Neurotherapeutics 7, 366377.
Lull, M.E. and Block, M.L. (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7, 354365.
Lyons, A., Downer, E.J., Crotty, S., Nolan, Y.M., Mills, K.H. and Lynch, M.A. (2007) CD200 ligand-receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. Journal of Neuroscience 27, 83098313.
Mallat, M. and Chamak, B. (1994) Brain macrophages: neurotoxic or neurotrophic effector cells? Journal of Leukocyte Biology 56, 416422.
Mallat, M., Marín-Teva, J.L. and Cheret, C. (2005) Phagocytosis in the developing CNS: more than clearing the corpses. Current Opinion in Neurobiology 15, 101107.
Marín-Teva, J.L., Cuadros, M.A., Calvente, R., Almendros, A. and Navascués, J. (1999) Naturally occurring cell death and migration of microglial precursors in the quail retina during normal development. Journal of Comparative Neurology 412, 255275.
Marín-Teva, J.L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N. and Mallat, M. (2004) Microglia promote the death of developing Purkinje cells. Neuron 41, 535547.
Mevorach, D., Mascarenhas, J.O., Gershov, D. and Elkon, K.B. (1998) Complement-dependent clearance of apoptotic cells by human macrophages. Journal of Experimental Medicine 188, 23132320.
Mizutani, M., Pino, P.A., Saederup, N., Charo, I.F., Ransohoff, R.M. and Cardona, A.E. (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. Journal of Immunology 188, 2936.
Morgan, S.C., Taylor, D.L. and Pocock, J.M. (2004) Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades. Journal of Neurochemistry 90, 89101.
Morioka, T. and Streit, W.J. (1991) Expression of immunomolecules on microglial cells following neonatal sciatic nerve axotomy. Journal of Neuroimmunology 35, 2130.
Moujahid, A., Navascués, J., Marín-Teva, J.L. and Cuadros, M.A. (1996) Macrophages during avian optic nerve development: relationship to cell death and differentiation into microglia. Anatomy and Embryology 193, 131144.
Mount, M.P., Lira, A., Grimes, D., Smith, P.D., Faucher, S., Slack, R. et al. (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. Journal of Neuroscience 27, 33283337.
Nakajima, K., Honda, S., Tohyama, Y., Imai, Y., Kohsaka, S. and Kurihara, T. (2001) Neurotrophin secretion from cultured microglia. Journal of Neuroscience Research 65, 322331.
Nakazawa, T., Hisatomi, T., Nakazawa, C., Noda, K., Maruyama, K., She, H. et al. (2007) Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proceedings of the National Academy of Sciences of the U.S.A. 104, 24252430.
Navascués, J., Moujahid, A., Almendros, A., Marín-Teva, J.L. and Cuadros, M.A. (1995) Origin of microglia in the quail retina: central-to-peripheral and vitreal-to-scleral migration of microglial precursors during development. Journal of Comparative Neurology 354, 209228.
Nedeljkovic, N., Bjelobaba, I., Subasic, S., Lavrnja, I., Pekovic, S., Stojkov, D. et al. (2006) Up-regulation of ectonucleotidase activity after cortical stab injury in rats. Cell Biology International 30, 541546.
Neher, J.J., Neniskyte, U., Zhao, J.W., Bal-Price, A., Tolkovsky, A.M. and Brown, G.C. (2011) Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. Journal of Immunology 186, 49734983.
Neniskyte, U., Neher, J.J. and Brown, G.C. (2011) Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia. Journal of Biological Chemistry 286, 3990439913.
Neumann, H., Kotter, M.R. and Franklin, R.J. (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132, 288295.
Nimmerjahn, A., Kirchhoff, F. and Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 13141318.
Noda, M., Doi, Y., Liang, J., Kawanokuchi, J., Sonobe, Y., Takeuchi, H. et al. (2011) Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. Journal of Biological Chemistry 286, 23082319.
O'Connor, T.M. and Wyttenbach, C.R. (1974) Cell death in the embryonic chick spinal cord. Journal of Cell Biology 60, 448459.
Ohsawa, K. and Kohsaka, S. (2011) Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia 59, 17931799.
Olah, M., Amor, S., Brouwer, N., Vinet, J., Eggen, B., Biber, K. et al. (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60, 306321.
Olah, M., Biber, K., Vinet, J. and Boddeke, H.W.G.M. (2011) Microglia phenotype diversity. CNS and Neurological Disorders-Drug Targets 10, 108118.
Oppenheim, R.W. (1989) The neurotrophic theory and naturally occurring motoneuron death. Trends in Neurosciences 12, 252255.
Oppenheim, R.W. (1991) Cell death during development of the nervous system. Annual Review of Neuroscience 14, 453501.
Park, K.W., Lee, D.Y., Joe, E.H., Kim, S.U. and Jin, B.K. (2005) Neuroprotective role of microglia expressing interleukin-4. Journal of Neuroscience Research 81, 397402.
Parnaik, R., Raff, M.C. and Scholes, J. (2000) Differences between the clearance of apoptotic cells by professional and non-professional phagocytes. Current Biology 10, 857860.
Pearson, H.E., Payne, B.R. and Cunningham, T.J. (1993) Microglial invasion and activation in response to naturally occurring neuronal degeneration in the ganglion cell layer of the postnatal cat retina. Developmental Brain Research 76, 249255.
Peri, F. and Nüsslein-Volhard, C. (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133, 916927.
Perry, V.H. and Gordon, S. (1991) Macrophages and the nervous system. International Review of Cytology 125, 203244.
Perry, V.H., Hume, D.A. and Gordon, S. (1985) Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313326.
Perry, V.H., Nicoll, J.A. and Holmes, C. (2010) Microglia in neurodegenerative disease. Nature Reviews Neurology 6, 193201.
Peter, C., Waibel, M., Radu, C.G., Yang, L.V., Witte, O.N., Schulze-Osthoff, K. et al. (2008) Migration to apoptotic ‘find-me’ signals is mediated via the phagocyte receptor G2A. Journal of Biological Chemistry 283, 52965305.
Piani, D., Frei, K., Do, K.Q., Cuenod, M. and Fontana, A. (1991) Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neuroscience Letters 133, 159162.
Piccinini, A.M. and Midwood, K.S. (2010) DAMPening inflammation by modulating TLR signalling. Mediators of Inflammation 2010, 672395, doi:10.1155/2010/672395.
Polazzi, E., Altamira, L.E., Eleuteri, S., Barbaro, R., Casadio, C., Contestabile, A. et al. (2009) Neuroprotection of microglial conditioned medium on 6-hydroxydopamine-induced neuronal death: role of transforming growth factor beta-2. Journal of Neurochemistry 110, 545556.
Prinz, M. and Mildner, A. (2011) Microglia in the CNS: immigrants from another world. Glia 59, 177187.
Prinz, M., Priller, J., Sisodia, S.S. and Ransohoff, R.M. (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neuroscience 13, 12271235.
Provis, J.M., Diaz, C.M. and Penfold, P.L. (1996) Microglia in human retina: a heterogeneous population with distinct ontogenies. Perspectives on Developmental Neurobiology 3, 213222.
Qin, L., Liu, Y., Wang, T., Wei, S.J., Block, M.L., Wilson, B. et al. (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. Journal of Biological Chemistry 279, 14151421.
Raff, M.C., Barres, B.A., Burne, J.F., Coles, H.S., Ishizaki, Y. and Jacobson, M.D. (1993) Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262, 695700.
Raivich, G., Bohatschek, M., Kloss, C.U., Werner, A., Jones, L.L. and Kreutzberg, G.W. (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Research Reviews 30, 77105.
Rakic, S. and Zecevic, N. (2000) Programmed cell death in the developing human telencephalon. European Journal of Neuroscience 12, 27212734.
Ransohoff, R.M. and Perry, V.H. (2009) Microglial physiology: unique stimuli, specialized responses. Annual Review of Immunology 27, 119145.
Ravichandran, K.S. (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. Journal of Experimental Medicine 207, 18071817.
Reddien, P.W., Cameron, S. and Horvitz, H.R. (2001) Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198202.
Rezaie, P. and Male, D. (1999) Colonisation of the developing human brain and spinal cord by microglia: a review. Microscopy Research and Technique 45, 359382.
Ribak, C.E., Shapiro, L.A., Perez, Z.D. and Spigelman, I. (2009) Microglia-associated granule cell death in the normal adult dentate gyrus. Brain Structure and Function 214, 2535.
Rigato, C., Buckinx, R., Le-Corronc, H., Rigo, J.M. and Legendre, P. (2011) Pattern of invasion of the embryonic mouse spinal cord by microglial cells at the time of the onset of functional neuronal networks. Glia 59, 675695.
Rutar, M., Natoli, R., Valter, K. and Provis, J.M. (2011) Early focal expression of the chemokine Ccl2 by Muller cells during exposure to damage-inducing bright continuous light. Investigative Ophthalmology and Visual Science 52, 23792388.
Ryu, J.K., Kim, J., Choi, S.H., Oh, Y.J., Lee, Y.B., Kim, S.U. et al. (2002) ATP-induced in vivo neurotoxicity in the rat striatum via P2 receptors. Neuroreport 13, 16111615.
Saijo, K. and Glass, C.K. (2011) Microglial cell origin and phenotypes in health and disease. Nature Reviews Immunology 11, 775787.
Sánchez-López, A.M., Cuadros, M.A., Calvente, R., Tassi, M., Marín-Teva, J.L. and Navascués, J. (2005) Activation of immature microglia in response to stab wound in embryonic quail retina. Journal of Comparative Neurology 492, 2033.
Santos, A.M., Calvente, R., Tassi, M., Carrasco, M.C., Martín-Oliva, D., Marín-Teva, J.L. et al. (2008) Embryonic and postnatal development of microglial cells in the mouse retina. Journal of Comparative Neurology 506, 224239.
Savill, J. and Fadok, V. (2000) Corpse clearance defines the meaning of cell death. Nature 407, 784788.
Sawada, M., Sawada, H. and Nagatsu, T. (2008) Effects of aging on neuroprotective and neurotoxic properties of microglia in neurodegenerative diseases. Neurodegenerative Diseases 5, 254256.
Schilling, M., Strecker, J.K., Schabitz, W.R., Ringelstein, E.B. and Kiefer, R. (2009) Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience 161, 806812.
Schlegelmilch, T., Henke, K. and Peri, F. (2011) Microglia in the developing brain: from immunity to behaviour. Current Opinion in Neurobiology 21, 510.
Sedel, F., Bechade, C., Vyas, S. and Triller, A. (2004) Macrophage-derived tumor necrosis factor α, an early developmental signal for motoneuron death. Journal of Neuroscience 24, 22362246.
Shan, S., Hong-Min, T., Yi, F., Jun-Peng, G., Yue, F., Yan-Hong, T. et al. (2011) New evidences for fractalkine/CX3CL1 involved in substantia nigral microglial activation and behavioral changes in a rat model of Parkinson's disease. Neurobiology of Aging 32, 443458.
Sierra, A., Encinas, J.M., Deudero, J.J., Chancey, J.H., Enikolopov, G., Overstreet-Wadiche, L.S. et al. (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483495.
Simard, A.R. and Rivest, S. (2007) Neuroprotective effects of resident microglia following acute brain injury. Journal of Comparative Neurology 504, 716729.
Sivakumar, V., Foulds, W.S., Luu, C.D., Ling, E.A. and Kaur, C. (2011) Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina. Journal of Pathology 224, 245260.
Smith, J.A., Das, A., Ray, S.K. and Banik, N.L. (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Research Bulletin 87, 1020.
Snider, W.D. (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627638.
Sorokin, S.P., Hoyt, R.F. Jr., Blunt, D.G. and McNelly, N.A. (1992) Macrophage development: II. Early ontogeny of macrophage populations in brain, liver, and lungs of rat embryos as revealed by a lectin marker. Anatomical Record 232, 527550.
Stone, T.W. (2002) Purines and neuroprotection. Advances in Experimental Medicine and Biology 513, 249280.
Streit, W.J. (2001) Microglia and macrophages in the developing CNS. Neurotoxicology 22, 619624.
Streit, W.J., Miller, K.R., Lopes, K.O. and Njie, E. (2008) Microglial degeneration in the aging brain – bad news for neurons? Frontiers in Bioscience 13, 34233438.
Takahashi, K., Rochford, C.D. and Neumann, H. (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. Journal of Experimental Medicine 201, 647657.
Takahashi, S., Ohshima, T., Hirasawa, M., Pareek, T.K., Bugge, T.H., Morozov, A. et al. (2010) Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration. American Journal of Pathology 176, 320329.
Tansey, M.G. and Goldberg, M.S. (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiology of Disease 37, 510518.
Taylor, S., Calder, C.J., Albon, J., Erichsen, J.T., Boulton, M.E. and Morgan, J.E. (2011) Involvement of the CD200 receptor complex in microglia activation in experimental glaucoma. Experimental Eye Research 92, 338343.
Thanos, S. (1991) The relationship of microglial cells to dying neurons during natural neuronal cell death and axotomy-induced degeneration of the rat retina. European Journal of Neuroscience 3, 11891207.
Thery, C., Chamak, B. and Mallat, M. (1991) Cytotoxic effect of brain macrophages on developing neurons. European Journal of Neuroscience 3, 11551164.
Truman, L.A., Ford, C.A., Pasikowska, M., Pound, J.D., Wilkinson, S.J., Dumitriu, I.E., et al. (2008) CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 50265036.
Upender, M.B. and Naegele, J.R. (1999) Activation of microglia during developmentally regulated cell death in the cerebral cortex. Developmental Neuroscience 21, 491505.
Valenciano, A.I., Boya, P. and de la Rosa, E.J. (2009) Early neural cell death: numbers and cues from the developing neuroretina. International Journal of Developmental Biology 53, 15151528.
van Rossum, D. and Hanisch, U.K. (2004) Microglia. Metabolic Brain Disease 19, 393411.
von Bernhardi, R., Tichauer, J.E. and Eugenin, J. (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. Journal of Neurochemistry 112, 10991114.
Wake, H., Moorhouse, A.J., Jinno, S., Kohsaka, S. and Nabekura, J. (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. Journal of Neuroscience 29, 39743980.
Wakselman, S., Bechade, C., Roumier, A., Bernard, D., Triller, A. and Bessis, A. (2008) Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. Journal of Neuroscience 28, 81388143.
Walter, L. and Neumann, H. (2009) Role of microglia in neuronal degeneration and regeneration. Seminars in Immunopathology 31, 513525.
Walton, N.M., Sutter, B.M., Laywell, E.D., Levkoff, L.H., Kearns, S.M., Marshall, G.P. 2nd, et al. (2006) Microglia instruct subventricular zone neurogenesis. Glia 54, 815825.
Wei, R. and Lin, C.M. (2009) Strain-dependent inflammatory responsiveness of rat microglial cells. Journal of Neuroimmunology 211, 2338.
Wink, M.R., Braganhol, E., Tamajusuku, A.S., Lenz, G., Zerbini, L.F., Libermann, T.A., et al. (2006) Nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) is the dominant ectonucleotidase expressed by rat astrocytes. Neuroscience 138, 421432.
Wirenfeldt, M., Babcock, A.A. and Vinters, H.V. (2011) Microglia – insights into immune system structure, function, and reactivity in the central nervous system. Histology and Histopathology 26, 519530.
Xiong, X., Barreto, G.E., Xu, L., Ouyang, Y.B., Xie, X. and Giffard, R.G. (2011) Increased brain injury and worsened neurological outcome in interleukin-4 knockout mice after transient focal cerebral ischemia. Stroke 42, 20262032.
Yeo, W. and Gautier, J. (2004) Early neural cell death: dying to become neurons. Developmental Biology 274, 233244.
Yuan, J. and Yankner, B.A. (2000) Apoptosis in the nervous system. Nature 407, 802809.
Zimmermann, H. and Braun, N. (1996) Extracellular metabolism of nucleotides in the nervous system. Journal of Autonomic Pharmacology 16, 397400.
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Neuron Glia Biology
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