Journal of Neuroimmune Pharmacology

, Volume 8, Issue 4, pp 807–823 | Cite as

Microglial Phenotype and Adaptation

  • B. J. L. Eggen
  • D. Raj
  • U.-K. Hanisch
  • H. W. G. M. Boddeke
INVITED REVIEW

Abstract

Microglia are the prime innate immune cells of the central nervous system. They can transit from a (so-called) resting state under homeostatic conditions towards a pro-inflammatory activation state upon homeostatic disturbances. Under neurodegenerative conditions, microglia have been largely perceived as neurotoxic cells. It is now becoming clear that resting microglia are not inactive but that they serve house-keeping functions. Moreover, microglia activity is not limited to proinflammatory responses, but covers a spectrum of reactive profiles. Depending on the actual situation, activated microglia display specific effector functions supporting inflammation, tissue remodeling, synaptic plasticity and neurogenesis. Many of these functions not only relate to the current state of the local neural environment but also depend on previous experience. In this review, we address microglia functions with respect to determining factors, phenotypic presentations, adaptation to environmental signals and aging. Finally, we point out primary mechanisms of microglia activation, which may comprise therapeutic targets to control neuro-inflammatory and neurodegenerative activity.

Keywords

Microglia Phenotype Immune priming Aging Tumors 

References

  1. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281–341PubMedCrossRefGoogle Scholar
  2. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H (2009) Purinergic signalling in the nervous system: an overview. Trends Neurosci 32:19–29PubMedCrossRefGoogle Scholar
  3. Abutbul S, Shapiro J, Szaingurten-Solodkin I, Levy N, Carmy Y, Baron R, Jung S, Monsonego A (2012) TGF-β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia 60:1160–1171PubMedCrossRefGoogle Scholar
  4. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FMV (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543PubMedCrossRefGoogle Scholar
  5. Allen IC, Scull MA, Moore CB, Holl EK, McElvania-TeKippe E, Taxman DJ, Guthrie EH, Pickles RJ, Ting JP (2009) The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30:556–565PubMedCrossRefGoogle Scholar
  6. Almolda B, Gonzalez B, Castellano B (2010) Activated microglial cells acquire an immature dendritic cell phenotype and may terminate the immune response in an acute model of EAE. J Neuroimmunol 223:39–54PubMedCrossRefGoogle Scholar
  7. Aloisi F (2001) Immune function of microglia. Glia 36:165–179PubMedCrossRefGoogle Scholar
  8. Aravalli RN, Peterson PK, Lokensgard JR (2007) Toll-like receptors in defense and damage of the central nervous system. J Neuroimmune Pharmacol 2:297–312PubMedCrossRefGoogle Scholar
  9. Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, Hudson CE, Cole MJ, Harrison JK, Bickford PC, Gemma C (2001) Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging 32:2030–2044CrossRefGoogle Scholar
  10. Barron KD (1995) The microglial cell. A historical review. J Neurol Sci 134:57–68PubMedCrossRefGoogle Scholar
  11. 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 56:69–77PubMedCrossRefGoogle Scholar
  12. Bedard A, Tremblay P, Chernomoretz A, Vallieres L (2007) Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation. Glia 55:777–789PubMedCrossRefGoogle Scholar
  13. Biber K, Neumann H, Inoue K, Boddeke HW (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30:596–602PubMedCrossRefGoogle Scholar
  14. Bilbo SD, Smith SH, Schwarz JM (2012) A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. J Neuroimmune Pharmacol 7:24–41PubMedCrossRefGoogle Scholar
  15. Biswas SK, Lopez-Collazo E (2009) Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 30:475–487PubMedCrossRefGoogle Scholar
  16. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69PubMedCrossRefGoogle Scholar
  17. Brockhaus J, Ilschner S, Banati RB, Kettenmann H (1993) Membrane properties of ameboid microglial cells in the corpus callosum slice from early postnatal mice. J Neurosci 13:4412–4421PubMedGoogle Scholar
  18. Bulloch K, Miller MM, Gal-Toth J, Milner TA, Gottfried-Blackmore A, Waters EM, Kaunzner UW, Liu K, Lindquist R, Nussenzweig MC, Steinman RM, McEwen BS (2008) CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J Comp Neurol 508:687–710PubMedCrossRefGoogle Scholar
  19. Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, Lawson R, Berry J, Krichevsky AM, Cudkowicz ME, Weiner HL (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063–3087PubMedCrossRefGoogle Scholar
  20. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924PubMedCrossRefGoogle Scholar
  21. Carson MJ, Reilly CR, Sutcliffe JG, Lo D (1998) Mature microglia resemble immature antigen-presenting cells. Glia 22:72–85PubMedCrossRefGoogle Scholar
  22. Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M (2003) Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 198:645–651PubMedCrossRefGoogle Scholar
  23. Chabot S, Williams G, Hamilton M, Sutherland G, Yong VW (1999) Mechanisms of IL-10 production in human microglia-T cell interaction. J Immunol 162:6819–6828PubMedGoogle Scholar
  24. Chen X, El Gazzar M, Yoza BK, McCall CE (2009) The NF-kappaB factor RelB and histone H3 lysine methyltransferase G9a directly interact to generate epigenetic silencing in endotoxin tolerance. J Biol Chem 284:27857–27865PubMedCrossRefGoogle Scholar
  25. Choi S, Aid S, Bosetti F (2009) The distinct roles of cyclooxygenase-1 and −2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30(4):174–181PubMedCrossRefGoogle Scholar
  26. Chuang HN, van Rossum D, Sieger D, Siam L, Klemm F, Bleckmann A, Bayerlová M, Farhat K, Scheffel J, Schulz M, Dehghani F, Stadelmann C, Hanisch UK, Binder C, Pukrop T (2013) Carcinoma cells misuse the host tissue damage response to invade the brain. Glia. doi:10.1002/glia.22518
  27. Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418PubMedCrossRefGoogle Scholar
  28. Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27–31PubMedCrossRefGoogle Scholar
  29. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284PubMedCrossRefGoogle Scholar
  30. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758PubMedCrossRefGoogle Scholar
  31. De Haas AH, Boddeke HW, Brouwer N, Biber K (2007) Optimized isolation enables ex vivo analysis of microglia from various central nervous system regions. Glia 13:1374–1384CrossRefGoogle Scholar
  32. De Haas AH, Boddeke HWGM, Biber K (2008) Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 56:888–894PubMedCrossRefGoogle Scholar
  33. del Río-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system, vol 2. Paul B. Hoeber Inc, New York, pp 483–534Google Scholar
  34. Dmowska M, Cybulska R, Schoenborn R, Piersiak T, Jaworska-Adamu J, Gawron A (2010) Behavioural and histological effects of preconditioning with lipopolysaccharide in epileptic rats. Neurochem Res 35:262–722PubMedCrossRefGoogle Scholar
  35. Durafourt BA, Moore CS, Zammit DA, Johnson TA, Zaguia F, Guiot MC, Bar-Or A, Antel JP (2012) Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia 60:717–727PubMedCrossRefGoogle Scholar
  36. Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci 94:4080–4085PubMedCrossRefGoogle Scholar
  37. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE (2008) G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J Biol Chem 283:32198–32208PubMedCrossRefGoogle Scholar
  38. Engelhardt B, Coisne C (2011) Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS 8:4–9PubMedCrossRefGoogle Scholar
  39. Esposito E, Di Matteo V, Benigno A, Pierucci M, Crescimanno G, Di Giovanni G (2007) Non-steroidal anti-inflammatory drugs in Parkinson’s disease. Exp Neurol 205:295–312PubMedCrossRefGoogle Scholar
  40. Etminan M, Carleton BC, Samii A (2008) Non-steroidal anti-inflammatory drug use and the risk of Parkinson disease: a retrospective cohort study. J Clin Neurosci 15:576–577PubMedCrossRefGoogle Scholar
  41. Faraco G, Pittelli M, Cavone L, Fossati S, Porcu M, Mascagni P, Fossati G, Moroni F, Chiarugi A (2009) Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Dis 36:269–279PubMedCrossRefGoogle Scholar
  42. Fedoroff S, Zhai R, Novak JP (1997) Microglia and astroglia have a common progenitor cell. J Neurosci Res 50:477–486PubMedCrossRefGoogle Scholar
  43. Felger JC, Abe T, Kaunzner UW, Gottfried-Blackmore A, Gal-Toth J, McEwen BS, Iadecola C, Bulloch K (2010) Brain dendritic cells in ischemic stroke: time course, activation state, and origin. Brain Behav Immun 24:724–737PubMedCrossRefGoogle Scholar
  44. Fenn AM, Henry CJ, Huang Y, Dugan A, Godbout JP (2012) Lipopolysaccharide-induced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav Immun 26:766–777PubMedCrossRefGoogle Scholar
  45. Ferrari D, Chiozzi P, Falzoni S, Dal Susino M, Collo G, Buell G, Di Virgilio F (1997) ATP-mediated cytotoxicity in microglial cells. Neuropharmacology 36:1295–1301PubMedCrossRefGoogle Scholar
  46. Fiebich BL, Biber K, Lieb K, van Calker D, Berger M, Bauer J, Gebicke-Haerter PJ (1996) Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. Glia 18:152–160PubMedCrossRefGoogle Scholar
  47. Fischer HG, Reichmann G (2001) Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 166:2717–27126PubMedGoogle Scholar
  48. Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M (2011) Selective transfer of exosomes from oligodendro-cytes to microglia by macropinocytosis. J Cell Sci 124:447–458PubMedCrossRefGoogle Scholar
  49. Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF (2006) mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging 27:717–722PubMedCrossRefGoogle Scholar
  50. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma’ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ (2012) Immunological Genome Consortium. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 11:1118–1128CrossRefGoogle Scholar
  51. Gavilán MP, Revilla E, Pintado C, Castaño A, Vizuete ML, Moreno-González I, Baglietto-Vargas D, Sánchez-Varo R, Vitorica J, Gutiérrez A, Ruano D (2007) Molecular and cellular characterization of the age-related neuroinflammatory processes occurring in normal rat hippocampus: potential relation with the loss of somatostatin GABAergic neurons. J Neurochem 103:984–996PubMedCrossRefGoogle Scholar
  52. Gendron FP, Chalimoniuk M, Strosznajder J, Shen S, Gonzalez FA, Weisman GA, Sun GY (2003) P2X7 nucleotide receptor activation enhances IFN _-induced type II nitric oxide synthase activity in BV-2 microglial cells. J Neurochem 87:344–352PubMedCrossRefGoogle Scholar
  53. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Guan Ng L, Stanley E, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845PubMedCrossRefGoogle Scholar
  54. Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19:1329–1331PubMedGoogle Scholar
  55. Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I (2006) T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80:797–801PubMedCrossRefGoogle Scholar
  56. Gomez Perdiguero E, Schulz C, Geissmann F (2013) Development and homeostasis of “resident” myeloid cells: the case of the microglia. Glia 61:12–20CrossRefGoogle Scholar
  57. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedCrossRefGoogle Scholar
  58. Gordon S (2007) The macrophage: past, present and future. Eur J Immunol 37:S9–S17PubMedCrossRefGoogle Scholar
  59. Gottfried-Blackmore A, Kaunzner UW, Idoyaga J, Felger JC, McEwen BS, Bulloch K (2009) Acute in vivo exposure to interferon-{gamma} enables resident brain dendritic cells to become effective antigen presenting cells. Proc Natl Acad Sci U S A 106:20918–20923PubMedCrossRefGoogle Scholar
  60. Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119:89–105PubMedCrossRefGoogle Scholar
  61. Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40:252–259PubMedCrossRefGoogle Scholar
  62. Greter M, Lelios I, Pelczar P, Hoeffel G, Price J, Leboeuf M, Kündig TM, Frei K, Ginhoux F, Merad M, Becher B (2012) Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37:1050–1060PubMedCrossRefGoogle Scholar
  63. Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA (2006) The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 99:1263–1272PubMedCrossRefGoogle Scholar
  64. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9:857–865PubMedCrossRefGoogle Scholar
  65. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155PubMedCrossRefGoogle Scholar
  66. Hanisch UK (2012) Factors controlling microglial activation. In: Kettenmann H, Ransom B (eds) Neuroglia, 3rd edn. Oxford University Press 48:614-625Google Scholar
  67. Hanisch UK (2013) Functional diversity of microglia—How heterogeneous are they to begin with? Front Cell Neurosci 7:65Google Scholar
  68. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedCrossRefGoogle Scholar
  69. Harding CV (1995) Intracellular organelles involved in antigen processing and the binding of peptides to class II MHC molecules. Semin Immunol 7:355–360PubMedCrossRefGoogle Scholar
  70. Haselkorn ML, Shellington D, Jackson E, Vagni VA, Janesko KL, Dubey RK, Gillespie DG, Cheng D, Bell MJ, Jenkins LW, Homanics GE, Schnermann J, Kochanek PM (2010) Adenosine A1 receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice. J Neurotrauma 27:901–910PubMedCrossRefGoogle Scholar
  71. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9:1512–1519PubMedCrossRefGoogle Scholar
  72. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y (2007) Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178:829–841PubMedCrossRefGoogle Scholar
  73. Heese K, Fiebich BL, Bauer J, Otten U (1997) Nerve growth factor (NGF) expression in rat microglia is induced by adenosine A2a receptors. Neurosci Lett 231:83–86PubMedCrossRefGoogle Scholar
  74. Heneka MT, Nadrigny F, Regen T, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP (2010) Locus ceruleus controls Alzheimer disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A 107:6058–6063PubMedCrossRefGoogle Scholar
  75. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 7434:674–678Google Scholar
  76. Hernán MA, Logroscino G, García Rodríguez LA (2006) Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease. Neurology 66:1097–1099PubMedCrossRefGoogle Scholar
  77. Hickey WF (1991) Migration of hematogenous cells through the bloodbrain barrier and the initiation of CNS inflammation. Brain Pathol 1:97–105PubMedCrossRefGoogle Scholar
  78. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771PubMedCrossRefGoogle Scholar
  79. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, Seaman WE (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109:1144–1156PubMedCrossRefGoogle Scholar
  80. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070PubMedCrossRefGoogle Scholar
  81. Hülper P, Schulz-Schaeffer W, Dullin C, Hoffmann P, Harper J, Kurtzberg L, Lonning S, Kugler W, Lakomek M, Erdlenbruch B (2011) Tumor localization of an anti-TGF-beta antibody and its effects on gliomas. Int J Oncol 38:51–59PubMedGoogle Scholar
  82. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8:261–279PubMedCrossRefGoogle Scholar
  83. Hwang IK, Lee CH, Li H, Yoo KY, Choi JH, Kim DW, Suh HW, Won MH (2008) Comparison of ionized calcium-binding adapter molecule 1 immunoreactivity of the hippocampal dentate gyrus and CA1 region in adult and aged dogs. Neurochem Res 33:1309–1315PubMedCrossRefGoogle Scholar
  84. Imbimbo BP (2009) An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer’s disease. Expert Opin Investig Drugs 18(8):1147–1168Google Scholar
  85. Inoue K (2006) The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 109:210–226PubMedCrossRefGoogle Scholar
  86. Inoue K, Tsuda M (2009) Microglia and neuropathic pain. Glia 57:1469–1479PubMedCrossRefGoogle Scholar
  87. Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, Morrison JP, Chen VS, Gris D, Matsushima GK, Ting JP (2010) The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci 30:15811–15820PubMedCrossRefGoogle Scholar
  88. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M, Gutierrez A, Vitorica J (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28:11650–11661PubMedCrossRefGoogle Scholar
  89. Jin MS, Lee JO (2008) Structures of the toll-like receptor family and its ligand complexes. Immunity 29:182–191PubMedCrossRefGoogle Scholar
  90. Jung S, Schwartz M (2012) Non-identical twins—microglia and monocyte-derived macrophages in acute injury and autoimmune inflammation. Front Immunol 3:89–92PubMedCrossRefGoogle Scholar
  91. Kaminski M, Bechmann I, Pohland M, Kiwit J, Nitsch R, Glumm J (2012) Migration of monocytes after intracerebral injection at entorhinal cortex lesion site. J Leukoc Biol 92:31–39PubMedCrossRefGoogle Scholar
  92. Kanneganti TD, Ozören N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Núñez G (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236PubMedCrossRefGoogle Scholar
  93. Kasckow J, Xiao C, Herman JP (2009) Glial glucocorticoid receptors in aged Fisher 344 (F344) and F344/Brown Norway rats. Exp Gerontol 44:335–343PubMedCrossRefGoogle Scholar
  94. 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 108:115–125PubMedCrossRefGoogle Scholar
  95. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384PubMedCrossRefGoogle Scholar
  96. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553PubMedCrossRefGoogle Scholar
  97. Kida S, Pantazis A, Weller RO (1993) CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19:480–488PubMedCrossRefGoogle Scholar
  98. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Hölscher C, Müller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16:273–280PubMedCrossRefGoogle Scholar
  99. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444PubMedCrossRefGoogle Scholar
  100. Kitamura Y, Taniguchi T, Kimura H, Nomura Y, Gebicke-Haerter PJ (2000) Interleukin-4-inhibited mRNA expression in mixed rat glial and in isolated microglial cultures. J Neuroimmunol 106:95–104PubMedCrossRefGoogle Scholar
  101. Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T (2010) CNS expression of anti inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP + PS1 bigenic mice. FASEB J 24:3093–3102PubMedCrossRefGoogle Scholar
  102. Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T (2012) AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP + PS1 mice. Gene Ther 19:724–733PubMedCrossRefGoogle Scholar
  103. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446:1091–1095PubMedCrossRefGoogle Scholar
  104. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170PubMedCrossRefGoogle Scholar
  105. Le Feuvre R, Brough D, Rothwell N (2002) Extracellular ATP and P2X7 receptors in neurodegeneration. Eur J Pharmacol 447:261–269PubMedCrossRefGoogle Scholar
  106. Ledeboer A, Brevé JJ, Poole S, Tilders FJ, Van Dam AM (2000) Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia 30:134–142PubMedCrossRefGoogle Scholar
  107. Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294–297PubMedCrossRefGoogle Scholar
  108. Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 69:94–103PubMedCrossRefGoogle Scholar
  109. Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G, Nitsch R, Weber JR (2008) A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 28:2320–2331PubMedCrossRefGoogle Scholar
  110. Leulier F, Lemaitre B (2008) Toll-like receptors: taking an evolutionary approach. Nat Rev Genet 9:165–178PubMedCrossRefGoogle Scholar
  111. Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma. Neuro-Oncol 14:958–978PubMedCrossRefGoogle Scholar
  112. Light AR, Wu Y, Hughen RW, Guthrie PB (2006) Purinergic receptors activating rapid intracellular Ca increases in microglia. Neuron Glia Biol 2:125–138PubMedCrossRefGoogle Scholar
  113. Longhi L, Gesuete R, Perego C, Ortolano F, Sacchi N, Villa P, Stocchetti N, De Simoni MG (2011) Long-lasting protection in brain trauma by endotoxin preconditioning. J Cereb Blood Flow Metab 31:1919–1929PubMedCrossRefGoogle Scholar
  114. 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 2Areceptor agonists: a novel therapy for neuropathic pain. J Neurosci 29:14015–14025PubMedCrossRefGoogle Scholar
  115. Lund S, Christensen KV, Hedtjärn M, Mortensen AL, Hagberg H, Falsig J, Hasseldam H, Schrattenholz A, Pörzgen P, Leist M (2006) The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions. J Neuroimmunol 180:71–87PubMedCrossRefGoogle Scholar
  116. Luo XG, Chen SD (2012) The changing phenotype of microglia from homeostasis to disease. Transl Neurodegener 1:1–9CrossRefGoogle Scholar
  117. Lynch AM, Walsh C, Delaney A, Nolan Y, Campbell VA, Lynch MA (2004) Lipopolysaccharide induced increase in signalling in hippocampus is abrogated by IL-10—a role for IL-1β? J Neurochem 88:635–646PubMedCrossRefGoogle Scholar
  118. Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA (2007) CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 27:8309–8313PubMedCrossRefGoogle Scholar
  119. Lyons A, Lynch AM, Downer EJ, Hanley R, O’Sullivan JB, Smith A, Lynch MA (2009) Fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway attentuates microglial activation in vivo and in vitro. J Neurochem 110:1547–1556PubMedCrossRefGoogle Scholar
  120. Mackaness GB (1964) The immunological basis of acquired cellular resistance. J Exp Med 120:105PubMedCrossRefGoogle Scholar
  121. Maher FO, Clarke RM, Kelly A, Nally RE, Lynch MA (2006) Interaction between interferon gamma and insulin-like growth factor-1 in hippocampus impacts on the ability of rats to sustain long-term potentiation. J Neurochem 96:1560–1571PubMedCrossRefGoogle Scholar
  122. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686PubMedCrossRefGoogle Scholar
  123. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232PubMedCrossRefGoogle Scholar
  124. Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kalin R, Van Rooijen N, Holmbeck K, Heppner FL, 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 U S A 106:12530–12535PubMedCrossRefGoogle Scholar
  125. Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265PubMedCrossRefGoogle Scholar
  126. Massengale M, Wagers AJ, Vogel H, Weissman IL (2005) Hematopoietic cells maintain hematopoietic fates upon entering the brain. J Exp Med 201:1579–1589PubMedCrossRefGoogle Scholar
  127. Matyszak MK, Denis-Donini S, Citterio S, Longhi R, Granucci F, Ricciardi-Castagnoli P (1999) Microglia induce myelin basic protein specific T cell anergy or T cell activation, according to their state of activation. Eur J Immunol 29:3063–3076PubMedCrossRefGoogle Scholar
  128. Melief J, Koning N, Schuurman KG, Van De Garde MD, Smolders J, Hoek RM, Van Eijk M, Hamann J, Huitinga I (2012) Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia 60:1506–1517PubMedCrossRefGoogle Scholar
  129. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2_ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553PubMedCrossRefGoogle Scholar
  130. Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, Pandey G, Leboeuf M, Elpek KG, Helft J, Hashimoto D, Chow A, Price J, Greter M, Bogunovic M, Bellemare-Pelletier A, Frenette PS, Randolph GJ, Turley SJ, Merad M (2012) Immunological Genome Consortium. Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol 13:888–899PubMedCrossRefGoogle Scholar
  131. Mirrione MM, Konomos DK, Gravanis I, Dewey SL, Aguzzi A, Heppner FL, Tsirka SE (2010) Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice. Neurobiol Dis 39:85–97PubMedCrossRefGoogle Scholar
  132. Mizoguchi K, Ikeda R, Shoji H, Tanaka Y, Maruyama W, Tabira T (2009) Aging attenuates glucocorticoid negative feedback in rat brain. Neuroscience 159:259–270PubMedCrossRefGoogle Scholar
  133. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedCrossRefGoogle Scholar
  134. Neumann H, Wekerle H (2013) Brain microglia: watchdogs with pedigree. Nat Neurosci 3:253–255CrossRefGoogle Scholar
  135. Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–295PubMedCrossRefGoogle Scholar
  136. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedCrossRefGoogle Scholar
  137. Nolan Y, Maher FO, Martin DS, Clarke RM, Brady MT, Bolton AE, Mills KH, Lynch MA (2005) Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus. J Biol Chem 280:9354–9362PubMedCrossRefGoogle Scholar
  138. Norden DM, Godbout JP (2013) Microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39:19–34PubMedCrossRefGoogle Scholar
  139. Norenberg W, Langosch JM, Gebicke-Haerter PJ, Illes P (1994) Characterization and possible function of adenosine 5 = −triphosphate receptors in activated rat microglia. Br J Pharmacol 111:942–950PubMedCrossRefGoogle Scholar
  140. O’Shea JJ, Murray PJ (2008) Cytokine signaling modules in inflammatory responses. Immunity 28:477–487PubMedCrossRefGoogle Scholar
  141. Ock J, Jeong J, Choi WS, Lee WH, Kim SH, Kim IK, Suk K (2007) Regulation of Toll-like receptor 4 expression and its signaling by hypoxia in cultured microglia. J Neurosci Res 85:1989–1995PubMedCrossRefGoogle Scholar
  142. Ogata T, Chuai M, Morino T, Yamamoto H, Nakamura Y, Schubert P (2003) Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2y receptors. Brain Res 981:174–183PubMedCrossRefGoogle Scholar
  143. Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59:278–292PubMedCrossRefGoogle Scholar
  144. Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K, Boddeke HWGM (2011a) Identification of a microglia phenotype supportive of remyelination. Glia 60:306–321PubMedCrossRefGoogle Scholar
  145. Olah M, Biber K, Vinet J, Boddeke HWGM (2011b) Microglia phenotype diversity. CNS Neurol Disord Drug Targets 10:108–118PubMedCrossRefGoogle Scholar
  146. Perry VH, Newman TA, Cunningham C (2003) The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 4:103–112PubMedCrossRefGoogle Scholar
  147. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167PubMedCrossRefGoogle Scholar
  148. Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP (2001) Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 168:144–154PubMedCrossRefGoogle Scholar
  149. Pocock JM, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30:527–535PubMedCrossRefGoogle Scholar
  150. Ponomarev ED, Novikova M, Maresz K, Shriver LP, Dittel BN (2005) Development of a culture system that supports adult microglial cell proliferation and maintenance in the resting state. J Immunol Methods 300:32–46PubMedCrossRefGoogle Scholar
  151. Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 40:10714–10721CrossRefGoogle Scholar
  152. Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL (2011) MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med 17:64–70PubMedCrossRefGoogle Scholar
  153. Popovich PG, Longbrake EE (2008) Can the immune system be harnessed to repair the CNS? Nat Rev Neurosci 9:481–493PubMedCrossRefGoogle Scholar
  154. Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U (2001) Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7:1356–1361PubMedCrossRefGoogle Scholar
  155. Prodinger C, Bunse J, Krüger M, Schiefenhövel F, Brandt C, Laman JD, Greter M, Immig K, Heppner F, Becher B, Bechmann I (2011) CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 121:445–458PubMedCrossRefGoogle Scholar
  156. Pukrop T, Dehghani F, Chuang HN, Lohaus R, Bayanga K, Heermann S, Regen T, van Rossum D, Klemm F, Schulz M, Siam L, Hoffmann A, Trümper L, Stadelmann C, Bechmann I, Hanisch UK, Binder C (2010) Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 58:1477–1489PubMedGoogle Scholar
  157. Püntener U, Booth SG, Perry VH, Teeling JL (2012) Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. J Neuroinflammation 9:146–149PubMedCrossRefGoogle Scholar
  158. Ramaglia V, Hughes TR, Donev RM, Ruseva MM, Wu X, Huitinga I, Baas F, Neal JW, Morgan BP (2012) C3-dependent mechanism of microglial priming relevant to multiple sclerosis. Proc Natl Acad Sci U S A 109:965–970PubMedCrossRefGoogle Scholar
  159. Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171PubMedCrossRefGoogle Scholar
  160. Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262PubMedCrossRefGoogle Scholar
  161. Rathinam VA, Vanaja SK, Fitzgerald KA (2012) Regulation of inflammasome signaling. Nat Immunol 13:332–333CrossRefGoogle Scholar
  162. Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170:1713–1724PubMedCrossRefGoogle Scholar
  163. Roberts JA, Vial C, Digby HR, Agboh KC, Wen H, Atterbury-Thomas A, Evans RJ (2006) Molecular properties of P2X receptors. Pflugers Arch 452:486–500PubMedCrossRefGoogle Scholar
  164. Robins HI, Peterson CG, Mehta MP (2003) Combined modality treatment for central nervous system malignancies. Semin Oncol 30:11–22PubMedCrossRefGoogle Scholar
  165. Rosenzweig HL, Lessov NS, Henshall DC, Minami M, Simon RP, Stenzel-Poore MP (2004) Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 35:2576–2581PubMedCrossRefGoogle Scholar
  166. Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL, Ransohoff RM, Charo IF (2010) Selective chemokine receptor usage by central nervous system myeloid cells in CCR2–red fluorescent protein knock-in mice. PLoS One 5:e13693PubMedCrossRefGoogle Scholar
  167. Santambrogio L, Belyanskaya SL, Fischer FR, Cipriani B, Brosnan CF, Ricciardi-Castagnoli P, Stern LJ, Strominger JL, Riese R (2001) Developmental plasticity of CNS microglia. Proc Natl Acad Sci U S A 98:6295–6300PubMedCrossRefGoogle Scholar
  168. Scheffel J, Regen T, van Rossum D, Seifert S, Ribes S, Nau R, Parsa R, Harris RA, Boddeke HWGM, Chuang HN, Pukrop T, Wessels JT, Jürgens T, Merkler D, Brück W, Schnaars M, Simons M, Kettenmann H, Hanisch UK (2012) Toll-like receptor activation reveals developmental reorganization and responder subsets of microglia. Glia 60:1930–1943PubMedCrossRefGoogle Scholar
  169. Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, Sutcliffe JG, Carson MJ (2002) Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem 83:1309–1320PubMedCrossRefGoogle Scholar
  170. Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74PubMedCrossRefGoogle Scholar
  171. Shiratori M, Tozaki-Saitoh H, Yoshitake M, Tsuda M, Inoue K (2010) P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways. J Neurochem 114:810–819PubMedCrossRefGoogle Scholar
  172. Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, McAlees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN (2013) The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497:498–502PubMedCrossRefGoogle Scholar
  173. Shuttleworth SJ, Bailey SG, Townsend PA (2011) Histone Deacetylase inhibitors: new promise in the treatment of immune and inflammatory diseases. Curr Drug Targets 11:1430–1438CrossRefGoogle Scholar
  174. Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55:412–424PubMedCrossRefGoogle Scholar
  175. Stenzel W, Müller U, Köhler G, Heppner FL, Blessing M, McKenzie AN, Brombacher F, Alber G (2009) IL-4/IL-13- dependent alternative activation of macrophages but not microglial cells is associated with uncontrolled cerebral cryptococcosis. Am J Pathol 174:486–496PubMedCrossRefGoogle Scholar
  176. Stichel CC, Luebbert H (2007) Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging 28:1507–1521PubMedCrossRefGoogle Scholar
  177. Streit WJ, Xue QS (2010) The brain’s aging immune system. Aging Dis 3:254–261Google Scholar
  178. Suuronen T, Huuskonen J, Pihlaja R, Kyrylenko S, Salminen A (2003) Regulation of microglial inflammatory response by histone deacetylase inhibitors. J Neurochem 87:407–416PubMedCrossRefGoogle Scholar
  179. Suuronen T, Huuskonen J, Nuutinen T, Salminen A (2006) Characterization of the pro-inflammatory signaling induced by protein acetylation in microglia. Neurochem Int 49:610–618PubMedCrossRefGoogle Scholar
  180. Thomas WE (1992) Brain macrophages: evaluation of microglia and their functions. Brain Res Rev 17:61–74PubMedCrossRefGoogle Scholar
  181. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783PubMedCrossRefGoogle Scholar
  182. Turrin NP, Rivest S (2006) Molecular and cellular immune mediators of neuroprotection. Mol Neurobiol 34:221–242PubMedCrossRefGoogle Scholar
  183. Ulvestad E, Williams K, Bjerkvig R, Tiekotter K, Antel J, Matre R (1994) Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen presenting cells. J Leukoc Biol 56:732–740PubMedGoogle Scholar
  184. Unger ER, Sung JH, Manivel JC, Chenggis ML, Blazar BR, Krivit W (1993) Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y chromosome specific in situ hybridization study. J Neuropathol Exp Neurol 52:460–470PubMedCrossRefGoogle Scholar
  185. Van Rossum D, Hanisch UK (2004) Microglia. Metab Brain Dis 19:393–411PubMedCrossRefGoogle Scholar
  186. van Zwam M, Huizinga R, Heijmans N, van Meurs M, Wierenga-Wolf AF, Melief MJ, Hintzen RQ, ’t Hart BA, Amor S, Boven LA, Laman JD (2009) Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J Pathol 217:543–551PubMedCrossRefGoogle Scholar
  187. Varvel NH, Grathwohl SA, Baumann F, Liebig C, Bosch A, Brawek B, Thal DR, Charo IF, Heppner FL, Aguzzi A, Garaschuk O, Ransohoff RM, Jucker M (2012) Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci U S A 109:18150–181555PubMedCrossRefGoogle Scholar
  188. Wahner AD, Bronstein JM, Bordelon YM, Ritz B (2007) Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology 69:1836–1842PubMedCrossRefGoogle Scholar
  189. Watts C (1997) Capture and processing of exogenous antigens for presentation on MHC molecules. Annu Rev Immunol 15:821–850PubMedCrossRefGoogle Scholar
  190. Wegiel J, Wiśniewski HM, Dziewiatkowski J, Tarnawski M, Kozielski R, Trenkner E, Wiktor-Jedrzejczak W (1998) Reduced number and altered morphology of microglial cells in colony stimulating factor-1–deficient osteoporotic op/op mice. Brain Res 804:135–139PubMedCrossRefGoogle Scholar
  191. Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD (2011) Microglia and memory: modulation by early-life infection. J Neurosci 31:15511–15521PubMedCrossRefGoogle Scholar
  192. Wong AM, Patel NV, Patel NK, Wei M, Morgan TE, de Beer MC, de Villiers WJ, Finch CE (2005) Macrosialin increases during normal brain aging are attenuated by caloric restriction. Neurosci Lett 390:76–80PubMedCrossRefGoogle Scholar
  193. Wynne AM, Henry CJ, Huang Y, Cleland A, Godbout JP (2010) Protracted downregulation of CX(3)CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav Immun 24:1190–1201PubMedCrossRefGoogle Scholar
  194. Xie Z, Morgan TE, Rozovsky I, Finch CE (2003) Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp Neurol 182:135–141PubMedCrossRefGoogle Scholar
  195. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T (2007) Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170:680–692PubMedCrossRefGoogle Scholar
  196. Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T (2008) Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes. J Immunol 181:3877–3886PubMedGoogle Scholar
  197. Yu JT, Lee CH, Yoo KY, Choi JH, Li H, Park OK, Yan B, Hwang IK, Kwon YG, Kim YM, Won MH (2010) Maintenance of anti-inflammatory cytokines and reduction of glial activation in the ischemic hippocampal CA1 region preconditioned with lipopolysaccharide. J Neurol Sci 296:69–78PubMedCrossRefGoogle Scholar
  198. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147:868–880PubMedCrossRefGoogle Scholar
  199. Zhou X, Spittau B, Krieglstein K (2012) TGFβ signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation 9:210–214PubMedCrossRefGoogle Scholar
  200. Ziegler G, Harhausen D, Schepers C, Hoffmann O, Röhr C, Prinz V, König J, Lehrach H, Nietfeld W, Trendelenburg G (2007) TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 359:574–579PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • B. J. L. Eggen
    • 1
  • D. Raj
    • 1
  • U.-K. Hanisch
    • 2
  • H. W. G. M. Boddeke
    • 1
  1. 1.Department of NeuroscienceUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  2. 2.Institute of NeuropathologyUniversity of GöttingenGöttingenGermany

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