Advertisement

Acta Neuropathologica

, Volume 119, Issue 1, pp 89–105 | Cite as

Microglia: biology and pathology

  • Manuel B. Graeber
  • Wolfgang J. Streit
Review

Abstract

The past 20 years have seen a gain in knowledge on microglia biology and microglia functions in disease that exceeds the expectations formulated when the microglia “immune network” was introduced. More than 10,000 articles have been published during this time. Important new research avenues of clinical importance have opened up such as the role of microglia in pain and in brain tumors. New controversies have also emerged such as the question of whether microglia are active or reactive players in neurodegenerative disease conditions, or whether they may be victims themselves. Premature commercial interests may be responsible for some of the confusion that currently surrounds microglia in both the Alzheimer and Parkinson’s disease research fields. A critical review of the literature shows that the concept of “(micro)glial inflammation” is still open to interpretation, despite a prevailing slant towards a negative meaning. Perhaps the most exciting foreseeable development concerns research on the role of microglia in synaptic plasticity, which is expected to yield an answer to the question whether microglia are the brain’s electricians. This review provides an analysis of the latest developments in the microglia field.

Keywords

Astrocytes Bone marrow-derived microglia Microglial development Neuroimmunology Pain Synaptic plasticity 

Notes

Acknowledgments

We would like to thank Dr Hua Yao for the electron micrographs and Dr Qing-Shan Xue for the preparation of the schematic drawing.

References

  1. 1.
    Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543PubMedGoogle Scholar
  2. 2.
    Albright AV, González-Scarano F (2004) Microarray analysis of activated mixed glial (microglia) and monocyte-derived macrophage gene expression. J Neuroimmunol 157:27–38PubMedGoogle Scholar
  3. 3.
    Appel SH, Beers DR, Henkel JS (2009) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol. doi: 10.1016/j.it.2009.09.003
  4. 4.
    Araque A (2008) Astrocytes process synaptic information. Neuron Glia Biol 4:3–10PubMedGoogle Scholar
  5. 5.
    Asheuer M, Pflumio F, Benhamida S, Dubart-Kupperschmitt A, Fouquet F, Imai Y, Aubourg P, Cartier N (2004) Human CD34+ cells differentiate into microglia and express recombinant therapeutic protein. Proc Natl Acad Sci USA 101:3557–3562PubMedGoogle Scholar
  6. 6.
    Banati RB, Myers R, Kreutzberg GW (1997) PK (‘peripheral benzodiazepine’)-binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol 26:77–82PubMedGoogle Scholar
  7. 7.
    Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R (2000) The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 123:2321–2337PubMedGoogle Scholar
  8. 8.
    Banati RB, Egensperger R, Maassen A, Hager G, Kreutzberg GW, Graeber MB (2004) Mitochondria in activated microglia in vitro. J Neurocytol 33:535–541PubMedGoogle Scholar
  9. 9.
    Beauvillain C, Donnou S, Jarry U, Scotet M, Gascan H, Delneste Y, Guermonprez P, Jeannin P, Couez D (2008) Neonatal and adult microglia cross-present exogenous antigens. Glia 56:69–77PubMedGoogle Scholar
  10. 10.
    Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 103:16021–16026PubMedGoogle Scholar
  11. 11.
    Bennett MR, Farnell L, Gibson WG (2009) P2X(7) regenerative-loop potentiation of glutamate synaptic transmission by microglia and astrocytes. J Theor Biol 261:1–16PubMedGoogle Scholar
  12. 12.
    Bertolotto A, Agresti C, Castello A, Manzardo E, Riccio A (1998) 5D4 keratan sulfate epitope identifies a subset of ramified microglia in normal central nervous system parenchyma. J Neuroimmunol 85:69–77PubMedGoogle Scholar
  13. 13.
    Billiards SS, Haynes RL, Folkerth RD, Trachtenberg FL, Liu LG, Volpe JJ, Kinney HC (2006) Development of microglia in the cerebral white matter of the human fetus and infant. J Comp Neurol 497:199–208PubMedGoogle Scholar
  14. 14.
    Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237PubMedGoogle Scholar
  15. 15.
    Blinzinger K, Kreutzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Z Zellforsch Mikroskop Anat 85:145–157Google Scholar
  16. 16.
    Boer K, Spliet WG, van Rijen PC, Redeker S, Troost D, Aronica E (2006) Evidence of activated microglia in focal cortical dysplasia. J Neuroimmunol 173:188–195PubMedGoogle Scholar
  17. 17.
    Boillée S, Cleveland DW (2008) Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. J Clin Invest 118:474–478PubMedGoogle Scholar
  18. 18.
    Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392PubMedGoogle Scholar
  19. 19.
    Borda JT, Alvarez X, Mohan M, Hasegawa A, Bernardino A, Jean S, Aye P, Lackner AA (2008) CD163, a marker of perivascular macrophages, is up-regulated by microglia in simian immunodeficiency virus encephalitis after haptoglobin-hemoglobin complex stimulation and is suggestive of breakdown of the blood-brain barrier. Am J Pathol 172:725–737PubMedGoogle Scholar
  20. 20.
    Bradesi S, Svensson CI, Steinauer J, Pothoulakis C, Yaksh TL, Mayer EA (2008) Role of spinal microglia in visceral hyperalgesia and NK1R up-regulation in a rat model of chronic stress. Gastroenterology. doi: 10.1053/j.gastro.2008.12.044
  21. 21.
    Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192PubMedGoogle Scholar
  22. 22.
    Butovsky O, Bukshpan S, Kunis G, Jung S, Schwartz M (2007) Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers. Mol Cell Neurosci 35:490–500PubMedGoogle Scholar
  23. 23.
    Byrnes KR, Garay J, Di Giovanni S, De Biase A, Knoblach SM, Hoffman EP, Movsesyan V, Faden AI (2006) Expression of two temporally distinct microglia-related gene clusters after spinal cord injury. Glia 53:420–433PubMedGoogle Scholar
  24. 24.
    Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB (2001) In vivo measurement of activated microglia in dementia. Lancet 358:461–467PubMedGoogle Scholar
  25. 25.
    Calderó J, Brunet N, Ciutat D, Hereu M, Esquerda JE (2009) Development of microglia in the chick embryo spinal cord: implications in the regulation of motoneuronal survival and death. J Neurosci Res. doi: 10.1002/jnr.22084
  26. 26.
    Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P (2009) Massive gliosis induced by interleukin-6 suppresses A{beta} deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. doi: 10.1096/fj.09-141754
  27. 27.
    Chauhan VS, Sterka DG, Furr SR, Young AB, Marriott I (2009) NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens. Glia 57:414–423PubMedGoogle Scholar
  28. 28.
    Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S (2006) Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 47:3595–3602PubMedGoogle Scholar
  29. 29.
    Chen J, Connor KM, Smith LE (2007) Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration. J Clin Invest 117:2758–2762PubMedGoogle Scholar
  30. 30.
    Chen L, Yang P, Kijlstra A (2002) Distribution, markers, and functions of retinal microglia. Ocul Immunol Inflamm 10:27–39PubMedGoogle Scholar
  31. 31.
    Chigurupati S, Wei Z, Belal C, Vandermey M, Kyriazis GA, Arumugam TV, Chan SL (2009) The homocysteine-inducible endoplasmic reticulum stress protein counteracts calcium store depletion and induction of CCAAT enhancer-binding protein homologous protein in a neurotoxin model of Parkinson disease. J Biol Chem 284:18323–18333PubMedGoogle Scholar
  32. 32.
    Choi SH, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM, Sisodia SS (2008) Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron 59:568–580PubMedGoogle Scholar
  33. 33.
    Clausen BH, Lambertsen KL, Babcock AA, Holm TH, Dagnaes-Hansen F, Finsen B (2008) Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflamm 5:46Google Scholar
  34. 34.
    Combadière C, Feumi C, Raoul W, Keller N, Rodéro M, Pézard A, Lavalette S, Houssier M, Jonet L, Picard E, Debré P, Sirinyan M, Deterre P, Ferroukhi T, Cohen SY, Chauvaud D, Jeanny JC, Chemtob S, Behar-Cohen F, Sennlaub F (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117:2920–2928PubMedGoogle Scholar
  35. 35.
    Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol 112:517–530PubMedGoogle Scholar
  36. 36.
    Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2:14. doi: 10.1186/1742-2094-2-14 PubMedGoogle Scholar
  37. 37.
    Croisier E, Moran LB, Graeber MB (2007) Expression of the scavenger receptor CD163 in Parkinson’s disease. Meeting of the British Neuropathological Society, 108th Meeting, Institute of Child Health, London UK, January 2007. Neuropathol Appl Neurobiol 33:266Google Scholar
  38. 38.
    D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor{alpha} signaling during peripheral organ inflammation. J Neurosci 29:2089–2102PubMedGoogle Scholar
  39. 39.
    Daginakatte GC, Gutmann DH (2007) Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genetics 16:1098–1112Google Scholar
  40. 40.
    Daginakatte GC, Gianino SM, Zhao NW, Parsadanian AS, Gutmann DH (2008) Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation. Cancer Res 68:10358–10366PubMedGoogle Scholar
  41. 41.
    Davoust N, Vuaillat C, Androdias G, Nataf S (2008) From bone marrow to microglia: barriers and avenues. Trends Immunol 29:227–234PubMedGoogle Scholar
  42. 42.
    de Jong EK, de Haas AH, Brouwer N, van Weering HR, Hensens M, Bechmann I, Pratley P, Wesseling E, Boddeke HW, Biber K (2008) Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J Neurochem 105:1726–1736PubMedGoogle Scholar
  43. 43.
    Deng YY, Lu J, Ling EA, Kaur C (2009) Monocyte chemoattractant protein-1 (MCP-1) produced via NF-kappaB signaling pathway mediates migration of amoeboid microglia in the periventricular white matter in hypoxic neonatal rats. Glia 57:604–621PubMedGoogle Scholar
  44. 44.
    Detloff MR, Fisher LC, McGaughy V, Longbrake EE, Popovich PG, Basso DM (2008) Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp Neurol 212:337–347PubMedGoogle Scholar
  45. 45.
    Dolman CL (1991) Microglia. In: Davis RL, Robertson DM (eds) Textbook of neuropathology. Williams and Wilkins, Baltimore, pp 141–163Google Scholar
  46. 46.
    Dominguez E, Rivat C, Pommier B, Mauborgne A, Pohl M (2008) JAK/STAT3 pathway is activated in spinal cord microglia after peripheral nerve injury and contributes to neuropathic pain development in rat. J Neurochem 107:50–60PubMedGoogle Scholar
  47. 47.
    Duke DC, Moran LB, Turkheimer FE, Banati R, Graeber MB (2004) Microglia in culture: what genes do they express? Dev Neurosci 26:30–37PubMedGoogle Scholar
  48. 48.
    Duke DC, Moran LB, Kalaitzakis ME, Deprez M, Dexter DT, Pearce RK, Graeber MB (2006) Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease. Neurogenetics 7:139–148PubMedGoogle Scholar
  49. 49.
    Ekdahl CT, Kokaia Z, Lindvall O (2008) Brain inflammation and adult neurogenesis: The dual role of microglia. Neuroscience. doi: 10.1016/j.neuroscience.2008.06.052
  50. 50.
    El Khoury J, Luster AD (2008) Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications. Trends Pharmacol Sci 29:626–632PubMedGoogle Scholar
  51. 51.
    Ethell DW, Shippy D, Cao C, Cracchiolo JR, Runfeldt M, Blake B, Arendash GW (2006) Abeta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer’s mice. Neurobiol Dis 23:351–361PubMedGoogle Scholar
  52. 52.
    Fan X, Luo G, Ming M, Pu P, Li L, Yang D, Le W (2009) Nurr1 expression and its modulation in microglia. Neuroimmunomodulation 16:162–170PubMedGoogle Scholar
  53. 53.
    Fendrick SE, Xue QS, Streit WJ (2007) Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu/Zn superoxide dismutase gene. J Neuroinflammation 4:9PubMedGoogle Scholar
  54. 54.
    Fernandez-Lizarbe S, Pascual M, Guerri C (2009) Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol. doi: 10.4049/jimmunol.0803590
  55. 55.
    Flügel A, Bradl M, Kreutzberg GW, Graeber MB (2001) Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. J Neurosci Res 66:74–82PubMedGoogle Scholar
  56. 56.
    Fulci G, Dmitrieva N, Gianni D, Fontana EJ, Pan X, Lu Y, Kaufman CS, Kaur B, Lawler SE, Lee RJ, Marsh CB, Brat DJ, Van Rooijen N, Stemmer-Rachamimov AO, Rachamimov AS, Hochberg FH, Weissleder R, Martuza RL, Chiocca EA (2007) Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses. Cancer Res 67:9398–9406PubMedGoogle Scholar
  57. 57.
    Gebicke-Haerter PJ (2005) Microarrays and expression profiling in microglia research and in inflammatory brain disorders. J Neurosci Res 81:327–341Google Scholar
  58. 58.
    Geranmayeh F, Scheithauer BW, Spitzer C, Meyer FB, Svensson-Engwall AC, Graeber MB (2007) Microglia in gemistocytic astrocytomas. Neurosurgery 60:159–166PubMedGoogle Scholar
  59. 59.
    Getts DR, Terry RL, Getts MT, Müller M, Rana S, Shrestha B, Radford J, Van Rooijen N, Campbell IL, King NJ (2008) Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J Exp Med 205:2319–2337PubMedGoogle Scholar
  60. 60.
    Glanzer JG, Enose Y, Wang T, Kadiu I, Gong N, Rozek W, Liu J, Schlautman JD, Ciborowski PS, Thomas MP, Gendelman HE (2007) Genomic and proteomic microglial profiling: pathways for neuroprotective inflammatory responses following nerve fragment clearance and activation. J Neurochem 102:627–645PubMedGoogle Scholar
  61. 61.
    Gowing G, Philips T, Van Wijmeersch B, Audet JN, Dewil M, Van Den Bosch L, Billiau AD, Robberecht W, Julien JP (2008) Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci 28:10234–10244PubMedGoogle Scholar
  62. 62.
    Gowing G, Lalancette-Hébert M, Audet JN, Dequen F, Julien JP (2009) Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Exp Neurol. doi: 10.1016/j.expneurol.2009.08.021
  63. 63.
    Graeber MB (2000) Glial inflammation in neurodegenerative diseases. In: 8th Annual Congress of the British Society for Immunology, Harrogate, 5–8 December 2000, Immunology Issue Supplement. Blackwell, Oxford (Abstract)Google Scholar
  64. 64.
    Graeber MB (2009) Biomarkers for Parkinson’s disease. Exp Neurol 216:249–253PubMedGoogle Scholar
  65. 65.
    Graeber MB, Streit WJ (1990) Microglia: immune network in the CNS. Brain Pathol 1:2–5PubMedGoogle Scholar
  66. 66.
    Graeber MB, Bise K, Mehraein P (1993) Synaptic stripping in the human facial nucleus. Acta Neuropathol 86:179–181PubMedGoogle Scholar
  67. 67.
    Graeber MB, Blakemore WF, Kreutzberg GW (2002) Cellular pathology of the central nervous system. In: Graham DI, Lantos PL (eds) Greenfield’s neuropathology, chap 3, 7th edn. Edward Arnold, London, pp 123–191Google Scholar
  68. 68.
    Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40:252–259PubMedGoogle Scholar
  69. 69.
    Graeber MB, López-Redondo F, Ikoma E, Ishikawa M, Imai Y, Nakajima K, Kreutzberg GW, Kohsaka S (1998) The microglia/macrophage response in the neonatal rat facial nucleus following axotomy. Brain Res 813:241–253PubMedGoogle Scholar
  70. 70.
    Grasbon-Frodl EM, Flügel A, Wolz P, Klinkert WEF, Kreutzberg GW, Graeber MB (1998) Untersuchungen zur Funktion von Mikroglia in Hirntumoren: Förderung des Wachstums von C6-Gliomzellen in vitro. Jahrestagung der Neuroonkologischen Arbeitsgemeinschaft der Deutschen Gesellschaft für Neurochirurgie in Dresden, 6–7 November 1998Google Scholar
  71. 71.
    Grathwohl SA, Kälin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. doi: 10.1038/nn.2432
  72. 72.
    Gupta N, Brown KE, Milam AH (2003) Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 76:463–471PubMedGoogle Scholar
  73. 73.
    Harry GJ, Kraft AD (2008) Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert Opin Drug Metab Toxicol 4:1265–1277PubMedGoogle Scholar
  74. 74.
    Hayakawa K, Mishima K, Nozako M, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Iwasaki K, Fujiwara M (2008) Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke 39:951–958PubMedGoogle Scholar
  75. 75.
    Henn A, Lund S, Hedtjärn M, Schrattenholz A, Pörzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX (Alternativen zu Tierexperimenten) 26:83–94Google Scholar
  76. 76.
    Hines DJ, Hines RM, Mulligan SJ, Macvicar BA (2009) Microglia processes block the spread of damage in the brain and require functional chloride channels. Glia. doi: 10.1002/glia.20874
  77. 77.
    Hochmeister S, Zeitelhofer M, Bauer J, Nicolussi EM, Fischer MT, Heinke B, Selzer E, Lassmann H, Bradl M (2008) After injection into the striatum, in vitro-differentiated microglia- and bone marrow-derived dendritic cells can leave the central nervous system via the blood stream. Am J Pathol 173:1669–1681PubMedGoogle Scholar
  78. 78.
    Horvath RJ, Nutile-McMenemy N, Alkaitis MS, DeLeo JA (2008) Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107:557–569PubMedGoogle Scholar
  79. 79.
    Hudson LC, Bragg DC, Tompkins MB, Meeker RB (2005) Astrocytes and microglia differentially regulate trafficking of lymphocyte subsets across brain endothelial cells. Brain Res 1058:148–160PubMedGoogle Scholar
  80. 80.
    Hunter RL, Cheng B, Choi DY, Liu M, Liu S, Cass WA, Bing G (2009) Intrastriatal lipopolysaccharide injection induces parkinsonism in C57/B6 mice. J Neurosci Res 87:1913–1921PubMedGoogle Scholar
  81. 81.
    Hwang SH, Yoo BC, Jung JS, Oh ES, Hwang J, Shin JA, Kim S, Cha S, Han IO (2009) Induction of glioma apoptosis by microglia-secreted molecules: the role of nitric oxide and cathepsin B. Biochim Biophys Acta. doi: 10.1016/j.bbamcr.2009.08.011
  82. 82.
    Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S (1996) A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 224:855–862PubMedGoogle Scholar
  83. 83.
    Inoue K, Tsuda M (2009) Microglia and neuropathic pain. Glia. doi: 10.1002/glia.20871
  84. 84.
    Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Mol Brain Res 57:1–9PubMedGoogle Scholar
  85. 85.
    Jana M, Palencia CA, Pahan K (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer’s disease. J Immunol 181:7254–7262PubMedGoogle Scholar
  86. 86.
    Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci USA 106:14063–14068PubMedGoogle Scholar
  87. 87.
    Joly S, Francke M, Ulbricht E, Beck S, Seeliger M, Hirrlinger P, Hirrlinger J, Lang KS, Zinkernagel M, Odermatt B, Samardzija M, Reichenbach A, Grimm C, Remé CE (2009) Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions. Am J Pathol 174:2310–2323PubMedGoogle Scholar
  88. 88.
    Jones LL, Banati RB, Graeber MB, Bonfanti L, Raivich G, Kreutzberg GW (1997) Population control of microglia: does apoptosis play a role? J Neurocytol 26:755–770PubMedGoogle Scholar
  89. 89.
    Jones N (2009) ‘Propaganda index’ proposed for medical literature. Nature Med 15:1100–1101PubMedGoogle Scholar
  90. 90.
    Kalm M, Lannering B, Björk-Eriksson T, Blomgren K (2009) Irradiation-induced loss of microglia in the young brain. J Neuroimmunol 206:70–75PubMedGoogle Scholar
  91. 91.
    Kaneko H, Nishiguchi KM, Nakamura M, Kachi S, Terasaki H (2008) Characteristics of bone marrow-derived microglia in the normal and injured retina. Invest Ophthalmol Vis Sci 49:4162–4168PubMedGoogle Scholar
  92. 92.
    Kataoka A, Tozaki-Saitoh H, Koga Y, Tsuda M, Inoue K (2009) Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT. J Neurochem 108:115–125PubMedGoogle Scholar
  93. 93.
    Kateb B, Van Handel M, Zhang L, Bronikowski MJ, Manohara H, Badie B (2007) Internalization of MWCNTs by microglia: possible application in immunotherapy of brain tumors. NeuroImage 37(Suppl 1):S9–S17PubMedGoogle Scholar
  94. 94.
    Kauppinen TM, Higashi Y, Suh SW, Escartin C, Nagasawa K, Swanson RA (2008) Zinc triggers microglial activation. J Neurosci 28:5827–5835PubMedGoogle Scholar
  95. 95.
    Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A (2008) Production and functions of IL-17 in microglia. J Neuroimmunol 194:54–61PubMedGoogle Scholar
  96. 96.
    Kobayashi K, Yamanaka H, Fukuoka T, Dai Y, Obata K, Noguchi K (2008) P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J Neurosci 28:2892–2902PubMedGoogle Scholar
  97. 97.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedGoogle Scholar
  98. 98.
    Ladeby R, Wirenfeldt M, Dalmau I, Gregersen R, García-Ovejero D, Babcock A, Owens T, Finsen B (2005) Proliferating resident microglia express the stem cell antigen CD34 in response to acute neural injury. Glia 50:121–131PubMedGoogle Scholar
  99. 99.
    Lalancette- Hébert M, Phaneuf D, Soucy G, Weng YC, Kriz J (2009) Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation. Brain. doi: 10.1093/brain/awn345
  100. 100.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170PubMedGoogle Scholar
  101. 101.
    Lee JE, Liang KJ, Fariss RN, Wong WT (2008) Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Invest Ophthalmol Vis Sci 49:4169–4176PubMedGoogle Scholar
  102. 102.
    Lee JK, Jin HK, Bae JS (2009) Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. Neurosci Lett 450:136–141PubMedGoogle Scholar
  103. 103.
    Leung E, Guo L, Bu J, Maloof M, Khoury JE, Geula C (2009) Microglia activation mediates fibrillar amyloid-beta toxicity in the aged primate cortex. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2009.02.025
  104. 104.
    Li W, Gao G, Guo Q, Jia D, Wang J, Wang X, He S, Liang Q (2009) Function and phenotype of microglia are determined by Toll-like receptor 2/Toll-like receptor 4 activation sequence. DNA Cell Biol. doi: 10.1089/dna.2009.0856
  105. 105.
    Liebrich M, Guo LH, Schluesener HJ, Schwab JM, Dietz K, Will BE, Meyermann R (2007) Expression of interleukin-16 by tumor-associated macrophages/activated microglia in high-grade astrocytic brain tumors. Arch Immunol Ther Exp (Warsz) 55:41–47Google Scholar
  106. 106.
    Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS (2001) Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. J Neurochem 77:182–189PubMedCrossRefGoogle Scholar
  107. 107.
    Liu C, Luo D, Streit WJ, Harrison JK (2008) CX3CL1 and CX3CR1 in the GL261 murine model of glioma: CX3CR1 deficiency does not impact tumor growth or infiltration of microglia and lymphocytes. J Neuroimmunol. doi: 10.1016/j.jneuroim.2008.04.016
  108. 108.
    Liu GJ, Nagarajah R, Banati RB, Bennett MR (2009) Glutamate induces directed chemotaxis of microglia. Eur J Neurosci 29:1108–1118PubMedGoogle Scholar
  109. 109.
    Liu H, Wang J, Sekiyama A, Tabira T (2008) Juzen-taiho-to, an herbal medicine, activates and enhances phagocytosis in microglia/macrophages. Tohoku J Exp Med 215:43–54PubMedGoogle Scholar
  110. 110.
    Liu Y, Hao W, Dawson A, Liu S, Fassbender K (2009) Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2. J Biol Chem 284:3691–3699PubMedGoogle Scholar
  111. 111.
    Loram LC, Harrison JA, Sloane EM, Hutchinson MR, Sholar P, Taylor FR, Berkelhammer D, Coats BD, Poole S, Milligan ED, Maier SF, Rieger J, Watkins LR (2009) Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: a novel therapy for neuropathic pain. J Neurosci 29:14015–14025PubMedGoogle Scholar
  112. 112.
    Lu H, Li Y, Shu M, Tang J, Huang Y, Zhou Y, Liang Y, Yan G (2009) Hypoxia-inducible factor-1alpha blocks differentiation of malignant gliomas. FEBS J. doi: 10.1111/j.1742-4658.2009.07441.x
  113. 113.
    Lünemann A, Ullrich O, Diestel A, Jöns T, Ninnemann O, Kovac A, Pohl EE, Hass R, Nitsch R, Hendrix S (2006) Macrophage/microglia activation factor expression is restricted to lesion-associated microglial cells after brain trauma. Glia 53:412–419PubMedGoogle Scholar
  114. 114.
    Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T, Zhang MR, Suzuki K, Suhara T (2007) Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res 1157:100–111PubMedGoogle Scholar
  115. 115.
    Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29:4252–4262PubMedGoogle Scholar
  116. 116.
    Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kälin R, Van Rooijen N, Holmbeck K, Heppner F, Kiwit J, Matyash V, Lehnardt S, Kaminska B, Glass R, Kettenmann H (2009) Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA. doi: 10.1073/pnas.0804273106
  117. 117.
    Marques CP, Cheeran MC, Palmquist JM, Hu S, Lokensgard JR (2008) Microglia are the major cellular source of inducible nitric oxide synthase during experimental herpes encephalitis. J Neurovirol 14:229–238PubMedGoogle Scholar
  118. 118.
    Marshall GP, Demir M, Steindler DA, Laywell ED (2008) Subventricular zone microglia possess a unique capacity for massive in vitro expansion. Glia 56:1799–1808PubMedGoogle Scholar
  119. 119.
    Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Ann Rev Immunol 27:451–483Google Scholar
  120. 120.
    Matsui T, Kakeda T (2008) IL-10 production is reduced by hypothermia but augmented by hyperthermia in rat microglia. J Neurotrauma 25:709–715PubMedGoogle Scholar
  121. 121.
    Mayo L, Jacob-Hirsch J, Amariglio N, Rechavi G, Moutin MJ, Lund FE, Stein R (2008) Dual role of CD38 in microglial activation and activation-induced cell death. J Immunol 181:92–103PubMedGoogle Scholar
  122. 122.
    McGeer PL, Itagaki S, McGeer EG (1988) Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76:550–557PubMedGoogle Scholar
  123. 123.
    Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Brück W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553PubMedGoogle Scholar
  124. 124.
    Mittelbronn M, Dietz K, Schluesener HJ, Meyermann R (2001) Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol 101:249–255PubMedGoogle Scholar
  125. 125.
    Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K (2008) Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 28:12775–12787PubMedGoogle Scholar
  126. 126.
    Monier A, Evrard P, Gressens P, Verney C (2006) Distribution and differentiation of microglia in the human encephalon during the first two trimesters of gestation. J Comp Neurol 499:565–582PubMedGoogle Scholar
  127. 127.
    Moran LB, Graeber MB (2004) The facial nerve axotomy model. Brain Res Rev 44:154–178PubMedGoogle Scholar
  128. 128.
    Moran LB, Graeber MB (2008) Towards a pathway definition of Parkinson’s disease: a complex disorder with links to cancer, diabetes and inflammation. Neurogenetics 9:1–13PubMedGoogle Scholar
  129. 129.
    Moran LB, Duke DC, Turkheimer FE, Banati RB, Graeber MB (2004) Towards a transcriptome definition of microglial cells. Neurogenetics 5:95–108PubMedGoogle Scholar
  130. 130.
    Moran LB, Duke DC, Graeber MB (2007) The microglial gene regulatory network activated by interferon-gamma. J Neuroimmunol 183:1–6PubMedGoogle Scholar
  131. 131.
    Morgan D (2009) The role of microglia in antibody-mediated clearance of amyloid-Beta from the brain. CNS Neurol Disord Drug Targets 8:7–15PubMedGoogle Scholar
  132. 132.
    Mundt AP, Winter C, Mueller S, Wuerfel J, Tysiak E, Schnorr J, Taupitz M, Heinz A, Juckel G (2009) Targeting activated microglia in Alzheimer’s pathology by intraventricular delivery of a phagocytosable MRI contrast agent in APP23 transgenic mice. NeuroImage 46:367–372PubMedGoogle Scholar
  133. 133.
    Nakajima K, Graeber MB, Sonoda M, Tohyama Y, Kohsaka S, Kurihara T (2006) In vitro proliferation of axotomized rat facial nucleus-derived activated microglia in an autocrine fashion. J Neurosci Res 84:348–359PubMedGoogle Scholar
  134. 134.
    Nakano T, Iseki K, Hozumi Y, Kawamae K, Wakabayashi I, Goto K (2009) Brain trauma induces expression of diacylglycerol kinase zeta in microglia. Neurosci Lett. doi: 10.1016/j.neulet.2009.06.001
  135. 135.
    Neumann H (2006) Microglia: a cellular vehicle for CNS gene therapy. J Clin Invest 116:2857–2860PubMedGoogle Scholar
  136. 136.
    Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, Dinkel K (2006) Microglia provide neuroprotection after ischemia. FASEB J 20:714–716PubMedGoogle Scholar
  137. 137.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedGoogle Scholar
  138. 138.
    Nixon K, Kim DH, Potts EN, He J, Crews FT (2008) Distinct cell proliferation events during abstinence after alcohol dependence: microglia proliferation precedes neurogenesis. Neurobiol Dis 31:218–229PubMedGoogle Scholar
  139. 139.
    Okada M, Saio M, Kito Y, Ohe N, Yano H, Yoshimura S, Iwama T, Takami T (2009) Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int J Oncol 34:1621–1627PubMedGoogle Scholar
  140. 140.
    Ovanesov MV, Ayhan Y, Wolbert C, Moldovan K, Sauder C, Pletnikov MV (2008) Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection. J Neuroinflammation 5:50PubMedGoogle Scholar
  141. 141.
    Park JY, Choi HJ, Prabagar MG, Choi WS, Kim SJ, Cheong C, Park CG, Chin CY, Kang YS (2009) The C-type lectin CD209b is expressed on microglia and it mediates the uptake of capsular polysaccharides of Streptococcus pneumoniae. Neurosci Lett 450:246–251PubMedGoogle Scholar
  142. 142.
    Peri F, Nüsslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927PubMedGoogle Scholar
  143. 143.
    Polazzi E, Contestabile A (2006) Overactivation of LPS-stimulated microglial cells by co-cultured neurons or neuron-conditioned medium. J Neuroimmunol 172:104–111PubMedGoogle Scholar
  144. 144.
    Power JH, Blumbergs PC (2009) Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol 117:63–73PubMedGoogle Scholar
  145. 145.
    Quik M, Campos C, Parameswaran N, Langston JW, McIntosh JM, Yeluashvili M (2009) Chronic nicotine treatment Increases nAChRs and microglial expression in monkey substantia nigra after nigrostriatal damage. J Mol Neurosci. doi: 10.1007/s12031-009-9265-9
  146. 146.
    Raivich G, Jones LL, Kloss CU, Werner A, Neumann H, Kreutzberg GW (1998) Immune surveillance in the injured nervous system: T-lymphocytes invade the axotomized mouse facial motor nucleus and aggregate around sites of neuronal degeneration. J Neurosci 18:5804–5816PubMedGoogle Scholar
  147. 147.
    Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, Cerny R, Gelman B, Thomas MP, Mosley RL, Gendelman HE (2007) Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem. doi: 10.1111/j.1471-4159.2007.05087.x
  148. 148.
    Ribot E, Bouzier-Sore AK, Bouchaud V, Miraux S, Delville MH, Franconi JM, Voisin P (2007) Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy. Cancer Gene Ther 14:724–737PubMedGoogle Scholar
  149. 149.
    Roberts ES, Masliah E, Fox HS (2004) CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE). J Neuropathol Exp Neurol 63:1255–1264PubMedGoogle Scholar
  150. 150.
    Rochefort N, Quenech’du N, Watroba L, Mallat M, Giaume C, Milleret C (2002) Microglia and astrocytes may participate in the shaping of visual callosal projections during postnatal development. J Physiol Paris 96:183–192PubMedGoogle Scholar
  151. 151.
    Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A (2007) Neuroinflammation in Alzheimer’s disease and Parkinson’s disease: are microglia pathogenic in either disorder? Int Rev Neurobiol 82:235–246PubMedGoogle Scholar
  152. 152.
    Romero-Sandoval EA, Horvath R, Landry RP, Deleo JA (2009) Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol Pain 5:25PubMedGoogle Scholar
  153. 153.
    Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59PubMedGoogle Scholar
  154. 154.
    Sanz JM, Chiozzi P, Ferrari D, Colaianna M, Idzko M, Falzoni S, Fellin R, Trabace L, Di Virgilio F (2009) Activation of microglia by amyloid beta requires P2X7 receptor expression. J Immunol 182:4378–4385PubMedGoogle Scholar
  155. 155.
    Sargsyan SA, Blackburn DJ, Barber SC, Monk PN, Shaw PJ (2009) Mutant SOD1 G93A microglia have an inflammatory phenotype and elevated production of MCP-1. Neuroreport. doi: 10.1097/WNR.0b013e328331e8fa
  156. 156.
    Sasahara M, Otani A, Oishi A, Kojima H, Yodoi Y, Kameda T, Nakamura H, Yoshimura N (2008) Activation of bone marrow-derived microglia promotes photoreceptor survival in inherited retinal degeneration. Am J Pathol 172:1693–1703PubMedGoogle Scholar
  157. 157.
    Sasaki A, Yamaguchi H, Horikoshi Y, Tanaka G, Nakazato Y (2004) Expression of glucose transporter 5 by microglia in human gliomas. Neuropathol Appl Neurobiol 30:447–455PubMedGoogle Scholar
  158. 158.
    Schmid CD, Melchior B, Masek K, Puntambekar SS, Danielson PE, Lo DD, Sutcliffe JG, Carson MJ (2009) Differential gene expression in LPS/IFNgamma activated microglia and macrophages: in vitro versus in vivo. J Neurochem 109(Suppl 1):117–125PubMedGoogle Scholar
  159. 159.
    Schwartz M, Butovsky O, Brück W, Hanisch U (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74PubMedGoogle Scholar
  160. 160.
    Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H (2008) IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1–42) by rat primary type 2 microglia. J Immunol 181:6503–6513PubMedGoogle Scholar
  161. 161.
    Simi A, Tsakiri N, Wang P, Rothwell NJ (2007) Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans 35:1122–1126PubMedGoogle Scholar
  162. 162.
    Simmons DA, Casale M, Alcon B, Pham N, Narayan N, Lynch G (2007) Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia 55:1074–1084PubMedGoogle Scholar
  163. 163.
    Slodzinski H, Moran LB, Michael GJ, Wang B, Novoselov S, Cheetham ME, Pearce RK, Graeber MB (2009) Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies. Clin Neuropathol 28:333–343PubMedGoogle Scholar
  164. 164.
    Somera-Molina KC, Nair S, Van Eldik LJ, Watterson DM, Wainwright MS (2009) Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model. Brain Res 1282:162–172PubMedGoogle Scholar
  165. 165.
    Soulet D, Rivest S (2008) Bone-marrow-derived microglia: myth or reality? Curr Opin Pharmacol 8:508–518PubMedGoogle Scholar
  166. 166.
    Streit W (2005) Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Rev 48:234–239PubMedGoogle Scholar
  167. 167.
    Streit WJ (2006) Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 29:506–510PubMedGoogle Scholar
  168. 168.
    Streit WJ, Kincaid-Colton CA (1995) The brain’s immune system. Sci Am 273(5):54–55, 58–61Google Scholar
  169. 169.
    Streit WJ, Xue QS (2009) Life and death of microglia. J NeuroImmune Pharmacol. doi: 10.1007/s11481-009-9163-5
  170. 170.
    Streit WJ, Graeber MB, Kreutzberg GW (1988) Functional plasticity of microglia: a review. Glia 1:301–307PubMedGoogle Scholar
  171. 171.
    Streit WJ, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485PubMedGoogle Scholar
  172. 172.
    Streit WJ, Miller KR, Lopes KO, Njie E (2008) Microglial degeneration in the aging brain—bad news for neurons? Front Biosci 13:3423–3438PubMedGoogle Scholar
  173. 173.
    Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212PubMedGoogle Scholar
  174. 174.
    Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ (2007) Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29:1690–1701PubMedGoogle Scholar
  175. 175.
    Sugama S, Takenouchi T, Fujita M, Conti B, Hashimoto M (2009) Differential microglial activation between acute stress and lipopolysaccharide treatment. J Neuroimmunol 207:24–31PubMedGoogle Scholar
  176. 176.
    Takamori Y, Mori T, Wakabayashi T, Nagasaka Y, Matsuzaki T, Yamada H (2009) Nestin-positive microglia in adult rat cerebral cortex. Brain Res. doi: 10.1016/j.brainres.2009.03.014
  177. 177.
    Takenouchi T, Nakai M, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Wei J, Sekigawa A, Sato M, Kojima S, Kitani H, Hashimoto M (2009) The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J Immunol 182:2051–2062PubMedGoogle Scholar
  178. 178.
    Tanuma N, Sakuma H, Sasaki A, Matsumoto Y (2006) Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis. Acta Neuropathol 112:195–204PubMedGoogle Scholar
  179. 179.
    Thacker MA, Clark AK, Bishop T, Grist J, Yip PK, Moon LD, Thompson SW, Marchand F, McMahon SB (2009) CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 13:263–272PubMedGoogle Scholar
  180. 180.
    Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA (2006) Microglia recognize double-stranded RNA via TLR3. J Immunol 176:3804–3812PubMedGoogle Scholar
  181. 181.
    Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K (2008) P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 28:4949–4956PubMedGoogle Scholar
  182. 182.
    Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff R (2007) Evidence for synaptic stripping by cortical microglia. Glia 55:360–368PubMedGoogle Scholar
  183. 183.
    Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K (2009) IFN-{gamma} receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci USA. doi: 10.1073/pnas.0810420106
  184. 184.
    Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (2008) Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268PubMedGoogle Scholar
  185. 185.
    Venneti S, Wagner AK, Wang G, Slagel SL, Chen X, Lopresti BJ, Mathis CA, Wiley CA (2007) The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging. Exp Neurol 207:118–127PubMedGoogle Scholar
  186. 186.
    Venneti S, Wang G, Nguyen J, Wiley CA (2008) The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders. J Neuropathol Exp Neurol 67:1001–1010PubMedGoogle Scholar
  187. 187.
    Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640PubMedGoogle Scholar
  188. 188.
    Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980PubMedGoogle Scholar
  189. 189.
    Walker DG, Link J, Lue LF, Dalsing-Hernandez JE, Boyes BE (2006) Gene expression changes by amyloid beta peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. J Leukocyte Biol 79:596–610PubMedGoogle Scholar
  190. 190.
    Wang J, Ohno-Matsui K, Yoshida T, Shimada N, Ichinose S, Sato T, Mochizuki M, Morita I (2009) Amyloid-beta up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration. J Cell Physiol. doi: 10.1002/jcp.21742
  191. 191.
    Wang X, Li C, Chen Y, Hao Y, Zhou W, Chen C, Yu Z (2008) Hypoxia enhances CXCR4 expression favoring microglia migration via HIF-1alpha activation. Biochem Biophys Res Commun 371:283–288PubMedGoogle Scholar
  192. 192.
    Wang XJ, Ye M, Zhang YH, Chen SD (2007) CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson’s disease. J NeuroImmune Pharmacol 2:259–264PubMedGoogle Scholar
  193. 193.
    Wesolowska A, Kwiatkowska A, Slomnicki L, Dembinski M, Master A, Sliwa M, Franciszkiewicz K, Chouaib S, Kaminska B (2008) Microglia-derived TGF-beta as an important regulator of glioblastoma invasion—an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene 27:918–930PubMedGoogle Scholar
  194. 194.
    Wirenfeldt M, Clare R, Tung S, Bottini A, Mathern GW, Vinters HV (2009) Increased activation of Iba1(+) microglia in pediatric epilepsy patients with Rasmussen’s encephalitis compared with cortical dysplasia and tuberous sclerosis complex. Neurobiol Dis. doi: 10.1016/j.nbd.2009.02.015
  195. 195.
    Wodarski R, Clark AK, Grist J, Marchand F, Malcangio M (2008) Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur J Pain. doi: 10.1016/j.ejpain.2008.09.010
  196. 196.
    Wu Z, Zhang J, Nakanishi H (2005) Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation. J Neuroimmunol 167:90–98PubMedGoogle Scholar
  197. 197.
    Zeilhofer HU (2008) Loss of glycinergic and GABAergic inhibition in chronic pain—contributions of inflammation and microglia. Int Immunopharmacol 8:182–187PubMedGoogle Scholar
  198. 198.
    Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 27:12396–12406PubMedGoogle Scholar
  199. 199.
    Zhang J, Cheng H, Chen J, Yi F, Li W, Luan R, Guo W, Lv A, Rao Z, Wang H (2009) Involvement of activated astrocyte and microglia of locus coeruleus in cardiac pain processing after acute cardiac injury. Neurol Res. doi: 10.1179/174313208X355486
  200. 200.
    Zhang Z, Artelt M, Burnet M, Trautmann K, Schluesener HJ (2006) Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury. Neuroscience 141:637–644PubMedGoogle Scholar
  201. 201.
    Zhao X, Grotta J, Gonzales N, Aronowski J (2008) Hematoma resolution as a therapeutic target. The role of microglia/macrophages. Stroke. doi: 10.1161/STROKEAHA.108.533158
  202. 202.
    Zhou Z, Peng X, Hao S, Fink DJ, Mata M (2008) HSV-mediated transfer of interleukin-10 reduces inflammatory pain through modulation of membrane tumor necrosis factor alpha in spinal cord microglia. Gene Ther 15:183–190PubMedGoogle Scholar
  203. 203.
    Zhu P, Hata R, Cao F, Gu F, Hanakawa Y, Hashimoto K, Sakanaka M (2008) Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function. FASEB J 22:3866–3877PubMedGoogle Scholar
  204. 204.
    Zou CG, Zhao YS, Gao SY, Li SD, Cao XZ, Zhang M, Zhang KQ (2009) Homocysteine promotes proliferation and activation of microglia. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2008.11.007

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Division of Neuropathology, Department of Pathology and Clinical Laboratory Medicine, Faculty of Medicine, Neurosciences CenterKing Fahad Medical CityRiyadhKingdom of Saudi Arabia
  2. 2.The Brain and Mind Research InstituteUniversity of SydneySydneyAustralia
  3. 3.Department of Neuroscience, McKnight Brain InstituteUniversity of Florida College of MedicineGainesvilleUSA

Personalised recommendations