Hostname: page-component-7d684dbfc8-kpkbf Total loading time: 0 Render date: 2023-09-29T21:54:51.100Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "coreDisableSocialShare": false, "coreDisableEcommerceForArticlePurchase": false, "coreDisableEcommerceForBookPurchase": false, "coreDisableEcommerceForElementPurchase": false, "coreUseNewShare": true, "useRatesEcommerce": true } hasContentIssue false

Microglia and neuronal cell death

Published online by Cambridge University Press:  01 March 2012

José L. Marín-Teva*
Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, Granada, Spain
Miguel A. Cuadros
Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, Granada, Spain
David Martín-Oliva
Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, Granada, Spain
Julio Navascués
Departamento de Biología Celular, Facultad de Ciencias, Universidad de Granada, Granada, Spain
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:


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.

Research Article
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)



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.CrossRefGoogle ScholarPubMed
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, 361374.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Ashwell, K. (1990) Microglia and cell death in the developing mouse cerebellum. Developmental Brain Research 55, 219230.CrossRefGoogle ScholarPubMed
Ashwell, K. (1991) The distribution of microglia and cell death in the fetal rat forebrain. Developmental Brain Research 58, 112.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Barde, Y.A. (1989) Trophic factors and neuronal survival. Neuron 2, 15251534.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Bessis, A., Bechade, C., Bernard, D. and Roumier, A. (2007) Microglial control of neuronal death and synaptic properties. Glia 55, 233238.CrossRefGoogle ScholarPubMed
Bianchi, M.E. (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. Journal of Leukocyte Biology 81, 15.CrossRefGoogle ScholarPubMed
Biber, K., Neumann, H., Inoue, K. and Boddeke, H.W. (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends in Neurosciences 30, 596602.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Block, M.L. and Hong, J.S. (2007) Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochemical Society Transactions 35, 11271132.CrossRefGoogle ScholarPubMed
Block, M.L., Zecca, L. and Hong, J.S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8, 5769.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
Brown, G.C. (2010) Nitric oxide and neuronal death. Nitric Oxide 23, 153165.CrossRefGoogle ScholarPubMed
Brown, G.C. and Neher, J.J. (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Molecular Neurobiology 41, 242247.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Cameron, B. and Landreth, G.E. (2010) Inflammation, microglia, and Alzheimer's disease. Neurobiology of Disease 37, 503509.CrossRefGoogle ScholarPubMed
Chan, W.Y., Kohsaka, S. and Rezaie, P. (2007) The origin and cell lineage of microglia: new concepts. Brain Research Reviews 53, 344354.CrossRefGoogle ScholarPubMed
Chanock, S.J., el Benna, J., Smith, R.M. and Babior, B.M. (1994) The respiratory burst oxidase. Journal of Biological Chemistry 269, 2451924522.Google ScholarPubMed
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.Google Scholar
Colton, C.A. (2009) Heterogeneity of microglial activation in the innate immune response in the brain. Journal of Neuroimmune Pharmacology 4, 399418.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Cuadros, M.A. and Navascués, J. (1998) The origin and differentiation of microglial cells during development. Progress in Neurobiology 56, 173189.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Cunha, R.A. (2005) Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade. Purinergic Signalling 1, 111134.CrossRefGoogle Scholar
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, 333346.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
David, S. and Kroner, A. (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nature Reviews Neuroscience 12, 388399.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
del Rio-Hortega, P. (1932) Microglia. InPenfield, W. (ed.) Cytology and Cellular Pathology of the Nervous System, vol. 2. Hafner, New York, pp. 483534.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Fiske, B.K. and Brunjes, P.C. (2000) Microglial activation in the developing rat olfactory bulb. Neuroscience 96, 807815.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Flavin, M.P., Zhao, G. and Ho, L.T. (2000) Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro. Glia 29, 347354.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Frade, J.M. and Barde, Y.A. (1998) Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 3541.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Gordon, S. and Taylor, P.R. (2005) Monocyte and macrophage heterogeneity. Nature Reviews Immunology 5, 953964.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Hanisch, U.K. (2002) Microglia as a source and target of cytokines. Glia 40, 140155.CrossRefGoogle ScholarPubMed
Hanisch, U.K. and Kettenmann, H. (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10, 13871394.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Herbomel, P., Thisse, B. and Thisse, C. (1999) Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126, 37353745.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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, 304309.3.0.CO;2-W>CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Kálmán, M. (1989) Dead cells can be phagocytosed by any neighboring cell in early developing rat brain. International Journal of Neuroscience 46, 139145.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Kettenmann, H., Hanisch, U.K., Noda, M. and Verkhratsky, A. (2011) Physiology of microglia. Physiological Reviews 91, 461553.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Kono, H. and Rock, K.L. (2008) How dying cells alert the immune system to danger. Nature Reviews Immunology 8, 279289.CrossRefGoogle ScholarPubMed
Kreutzberg, G. W. (1996) Microglia: a sensor for pathological events in the CNS. Trends in Neurosciences 19, 312318.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Kumar, H., Kawai, T. and Akira, S. (2011) Pathogen recognition by the innate immune system. International Reviews of Immunology 30, 1634.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Lauber, K., Blumenthal, S.G., Waibel, M. and Wesselborg, S. (2004) Clearance of apoptotic cells: getting rid of the corpses. Molecular Cell 14, 277287.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Lehnardt, S. (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58, 253263.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Lichanska, A.M. and Hume, D.A. (2000) Origins and functions of phagocytes in the embryo. Experimental Hematology 28, 601611.CrossRefGoogle ScholarPubMed
Liu, M. and Bing, G. (2011) Lipopolysaccharide animal models for Parkinson's disease. Parkinson's Disease 2011, 327089, doi: 10.4061/2011/327089.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Loane, D.J. and Byrnes, K.R. (2010) Role of microglia in neurotrauma. Neurotherapeutics 7, 366377.CrossRefGoogle ScholarPubMed
Lull, M.E. and Block, M.L. (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7, 354365.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Mallat, M. and Chamak, B. (1994) Brain macrophages: neurotoxic or neurotrophic effector cells? Journal of Leukocyte Biology 56, 416422.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 255275.3.0.CO;2-H>CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Morioka, T. and Streit, W.J. (1991) Expression of immunomolecules on microglial cells following neonatal sciatic nerve axotomy. Journal of Neuroimmunology 35, 2130.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Neumann, H., Kotter, M.R. and Franklin, R.J. (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132, 288295.CrossRefGoogle ScholarPubMed
Nimmerjahn, A., Kirchhoff, F. and Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 13141318.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
O'Connor, T.M. and Wyttenbach, C.R. (1974) Cell death in the embryonic chick spinal cord. Journal of Cell Biology 60, 448459.CrossRefGoogle ScholarPubMed
Ohsawa, K. and Kohsaka, S. (2011) Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia 59, 17931799.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Olah, M., Biber, K., Vinet, J. and Boddeke, H.W.G.M. (2011) Microglia phenotype diversity. CNS and Neurological Disorders-Drug Targets 10, 108118.CrossRefGoogle ScholarPubMed
Oppenheim, R.W. (1989) The neurotrophic theory and naturally occurring motoneuron death. Trends in Neurosciences 12, 252255.CrossRefGoogle ScholarPubMed
Oppenheim, R.W. (1991) Cell death during development of the nervous system. Annual Review of Neuroscience 14, 453501.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Perry, V.H. and Gordon, S. (1991) Macrophages and the nervous system. International Review of Cytology 125, 203244.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Perry, V.H., Nicoll, J.A. and Holmes, C. (2010) Microglia in neurodegenerative disease. Nature Reviews Neurology 6, 193201.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Piccinini, A.M. and Midwood, K.S. (2010) DAMPening inflammation by modulating TLR signalling. Mediators of Inflammation 2010, 672395, doi:10.1155/2010/672395.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Prinz, M. and Mildner, A. (2011) Microglia in the CNS: immigrants from another world. Glia 59, 177187.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Rakic, S. and Zecevic, N. (2000) Programmed cell death in the developing human telencephalon. European Journal of Neuroscience 12, 27212734.CrossRefGoogle ScholarPubMed
Ransohoff, R.M. and Perry, V.H. (2009) Microglial physiology: unique stimuli, specialized responses. Annual Review of Immunology 27, 119145.CrossRefGoogle ScholarPubMed
Ravichandran, K.S. (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. Journal of Experimental Medicine 207, 18071817.CrossRefGoogle ScholarPubMed
Reddien, P.W., Cameron, S. and Horvitz, H.R. (2001) Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198202.CrossRefGoogle ScholarPubMed
Rezaie, P. and Male, D. (1999) Colonisation of the developing human brain and spinal cord by microglia: a review. Microscopy Research and Technique 45, 359382.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Saijo, K. and Glass, C.K. (2011) Microglial cell origin and phenotypes in health and disease. Nature Reviews Immunology 11, 775787.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Savill, J. and Fadok, V. (2000) Corpse clearance defines the meaning of cell death. Nature 407, 784788.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Schlegelmilch, T., Henke, K. and Peri, F. (2011) Microglia in the developing brain: from immunity to behaviour. Current Opinion in Neurobiology 21, 510.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Simard, A.R. and Rivest, S. (2007) Neuroprotective effects of resident microglia following acute brain injury. Journal of Comparative Neurology 504, 716729.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Snider, W.D. (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627638.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Stone, T.W. (2002) Purines and neuroprotection. Advances in Experimental Medicine and Biology 513, 249280.CrossRefGoogle ScholarPubMed
Streit, W.J. (2001) Microglia and macrophages in the developing CNS. Neurotoxicology 22, 619624.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Thery, C., Chamak, B. and Mallat, M. (1991) Cytotoxic effect of brain macrophages on developing neurons. European Journal of Neuroscience 3, 11551164.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Upender, M.B. and Naegele, J.R. (1999) Activation of microglia during developmentally regulated cell death in the cerebral cortex. Developmental Neuroscience 21, 491505.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
van Rossum, D. and Hanisch, U.K. (2004) Microglia. Metabolic Brain Disease 19, 393411.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Walter, L. and Neumann, H. (2009) Role of microglia in neuronal degeneration and regeneration. Seminars in Immunopathology 31, 513525.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Wei, R. and Lin, C.M. (2009) Strain-dependent inflammatory responsiveness of rat microglial cells. Journal of Neuroimmunology 211, 2338.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Yeo, W. and Gautier, J. (2004) Early neural cell death: dying to become neurons. Developmental Biology 274, 233244.CrossRefGoogle ScholarPubMed
Yuan, J. and Yankner, B.A. (2000) Apoptosis in the nervous system. Nature 407, 802809.CrossRefGoogle Scholar
Zimmermann, H. and Braun, N. (1996) Extracellular metabolism of nucleotides in the nervous system. Journal of Autonomic Pharmacology 16, 397400.CrossRefGoogle Scholar