Skip to main content

Advertisement

Log in

The Multifaceted Profile of Activated Microglia

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Although relatively neglected previously, research efforts in the past decade or so have identified a pivotal role for glial cells in regulating neuronal function. Particular emphasis has been placed on increasing our understanding of the function of microglia because a change from the ramified “resting” state of these cells has been associated with the pathogenesis of several neurodegenerative diseases, notably Alzheimer’s disease. However, it is not clear whether activation of microglia and the associated inflammatory changes play a part in triggering disease processes or whether cell activation is a response to the early changes associated with the disease. In either case, the possibility exists that modulation of microglial activation may be beneficial in some circumstances, underlying the need to pursue research in this area. The original morphological categorization of microglia by Del Rio Hortega into ameboid, ramified, and intermediate forms, must now be elaborated to encompass a functional description. The evidence which has been generated recently suggests that microglia are probably never in a “resting” state and that several intermediate transitional states, based on function and morphology, probably exist. A more complete understanding of these states and the triggers which lead to a change from one to another state, and the factors which modulate the molecular switch that determines the persistence of the “activated” state remain to be identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313

    PubMed  CAS  Google Scholar 

  2. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170

    PubMed  CAS  Google Scholar 

  3. Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405–415

    PubMed  CAS  Google Scholar 

  4. Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 75:165–173

    PubMed  CAS  Google Scholar 

  5. McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 21:195–218

    PubMed  CAS  Google Scholar 

  6. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212

    PubMed  Google Scholar 

  7. Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE (1998) Glial–neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol 8:65–72

    PubMed  CAS  Google Scholar 

  8. Kato H, Kogure K, Liu XH, Araki T, Itoyama Y (1996) Progressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat. Brain Res 734:203–212

    PubMed  CAS  Google Scholar 

  9. Aloisi F (2001) Immune function of microglia. Glia 36:165–179

    PubMed  CAS  Google Scholar 

  10. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    PubMed  CAS  Google Scholar 

  11. Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20:269–287

    PubMed  CAS  Google Scholar 

  12. Wu CY, Kaur C, Sivakumar V, Lu J, Ling EA (2009) Kv1.1 expression in microglia regulates production and release of proinflammatory cytokines, endothelins and nitric oxide. Neuroscience 158:1500–1508

    PubMed  CAS  Google Scholar 

  13. Fordyce CB, Jagasia R, Zhu X, Schlichter LC (2005) Microglia Kv1.3 channels contribute to their ability to kill neurons. J Neurosci 25:7139–7149

    PubMed  CAS  Google Scholar 

  14. Persson M, Brantefjord M, Hansson E, Ronnback L (2005) Lipopolysaccharide increases microglial GLT-1 expression and glutamate uptake capacity in vitro by a mechanism dependent on TNF-alpha. Glia 51:111–120

    PubMed  Google Scholar 

  15. Chao CC, Gekker G, Hu S, Peterson PK (1994) Human microglial cell defense against Toxoplasma gondii. The role of cytokines. J Immunol 152:1246–1252

    PubMed  CAS  Google Scholar 

  16. Benedetto N, Auriault C (2002) Prolactin–cytokine network in the defence against Acanthamoeba castellanii in murine microglia [corrected]. Eur Cytokine Netw 13:447–455

    PubMed  CAS  Google Scholar 

  17. Bruce-Keller AJ (1999) Microglial–neuronal interactions in synaptic damage and recovery. J Neurosci Res 58:191–201

    PubMed  CAS  Google Scholar 

  18. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    PubMed  CAS  Google Scholar 

  19. Sasaki A, Hirato J, Nakazato Y (1993) Immunohistochemical study of microglia in the Creutzfeldt-Jakob diseased brain. Acta Neuropathol (Berl) 86:337–344

    CAS  Google Scholar 

  20. Streit WJ, Graeber MB, Kreutzberg GW (1989) Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury. Exp Neurol 105:115–126

    PubMed  CAS  Google Scholar 

  21. Beyer M, Gimsa U, Eyupoglu IY, Hailer NP, Nitsch R (2000) Phagocytosis of neuronal or glial debris by microglial cells: upregulation of MHC class II expression and multinuclear giant cell formation in vitro. Glia 31:262–266

    PubMed  CAS  Google Scholar 

  22. van Rossum D, Hilbert S, Strassenburg S, Hanisch UK, Bruck W (2008) Myelin-phagocytosing macrophages in isolated sciatic and optic nerves reveal a unique reactive phenotype. Glia 56:271–283

    PubMed  Google Scholar 

  23. Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292

    PubMed  CAS  Google Scholar 

  24. Matsumoto Y, Fujiwara M (1986) In situ detection of class I and II major histocompatibility complex antigens in the rat central nervous system during experimental allergic encephalomyelitis. An immunohistochemical study. J Neuroimmunol 12:265–277

    PubMed  CAS  Google Scholar 

  25. McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG (1993) Microglia in degenerative neurological disease. Glia 7:84–92

    PubMed  CAS  Google Scholar 

  26. Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202:13–23

    PubMed  CAS  Google Scholar 

  27. Woodroofe MN, Sarna GS, Wadhwa M, Hayes GM, Loughlin AJ, Tinker A, Cuzner ML (1991) Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol 33:227–236

    PubMed  CAS  Google Scholar 

  28. Sedgwick JD, Ford AL, Foulcher E, Airriess R (1998) Central nervous system microglial cell activation and proliferation follows direct interaction with tissue-infiltrating T cell blasts. J Immunol 160:5320–5330

    PubMed  CAS  Google Scholar 

  29. Lyons A, Griffin RJ, Costelloe CE, Clarke RM, Lynch MA (2007) IL-4 attenuates the neuroinflammation induced by amyloid-beta in vivo and in vitro. J Neurochem 101:771–781

    PubMed  CAS  Google Scholar 

  30. 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 96:1560–1571

    PubMed  CAS  Google Scholar 

  31. Vass K, Lassmann H (1990) Intrathecal application of interferon gamma. Progressive appearance of MHC antigens within the rat nervous system. Am J Pathol 137:789–800

    PubMed  CAS  Google Scholar 

  32. Benveniste EN, Nguyen VT, Wesemann DR (2004) Molecular regulation of CD40 gene expression in macrophages and microglia. Brain Behav Immun 18:7–12

    PubMed  CAS  Google Scholar 

  33. Aloisi F (1999) The role of microglia and astrocytes in CNS immune surveillance and immunopathology. Adv Exp Med Biol 468:123–133

    PubMed  CAS  Google Scholar 

  34. Cho BP, Song DY, Sugama S, Shin DH, Shimizu Y, Kim SS, Kim YS, Joh TH (2006) Pathological dynamics of activated microglia following medial forebrain bundle transection. Glia 53:92–102

    PubMed  Google Scholar 

  35. Hava DL, van der Wel N, Cohen N et al (2008) Evasion of peptide, but not lipid antigen presentation, through pathogen-induced dendritic cell maturation. Proc Natl Acad Sci U S A 105:11281–11286

    PubMed  CAS  Google Scholar 

  36. Hamo L, Stohlman SA, Otto-Duessel M, Bergmann CC (2007) Distinct regulation of MHC molecule expression on astrocytes and microglia during viral encephalomyelitis. Glia 55:1169–1177

    PubMed  Google Scholar 

  37. Bhatia S, Edidin M, Almo SC, Nathenson SG (2006) B7-1 and B7-2: similar costimulatory ligands with different biochemical, oligomeric and signaling properties. Immunol Lett 104:70–75

    PubMed  CAS  Google Scholar 

  38. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548

    PubMed  Google Scholar 

  39. Wolf SA, Gimsa U, Bechmann I, Nitsch R (2001) Differential expression of costimulatory molecules B7-1 and B7-2 on microglial cells induced by Th1 and Th2 cells in organotypic brain tissue. Glia 36:414–420

    PubMed  CAS  Google Scholar 

  40. Ponomarev ED, Shriver LP, Dittel BN (2006) CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation. J Immunol 176:1402–1410

    PubMed  CAS  Google Scholar 

  41. Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98

    PubMed  CAS  Google Scholar 

  42. 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 99:1263–1272

    PubMed  CAS  Google Scholar 

  43. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155

    PubMed  Google Scholar 

  44. Zeinstra E, Wilczak N, De Keyser J (2003) Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2. J Neuroimmunol 135:166–171

    PubMed  CAS  Google Scholar 

  45. Streit WJ, Walter SA, Pennell NA (1999) Reactive microgliosis. Prog Neurobiol 57:563–581

    PubMed  CAS  Google Scholar 

  46. Nagai A, Mishima S, Ishida Y, Ishikura H, Harada T, Kobayashi S, Kim SU (2005) Immortalized human microglial cell line: phenotypic expression. J Neurosci Res 81:342–348

    PubMed  CAS  Google Scholar 

  47. Solovjov DA, Pluskota E, Plow EF (2005) Distinct roles for the alpha and beta subunits in the functions of integrin alphaMbeta2. J Biol Chem 280:1336–1345

    PubMed  CAS  Google Scholar 

  48. Weber C, Erl W, Weber KS, Weber PC (1997) HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 30:1212–1217

    PubMed  CAS  Google Scholar 

  49. Reichert F, Rotshenker S (2003) Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages. Neurobiol Dis 12:65–72

    PubMed  CAS  Google Scholar 

  50. Smith ME (2001) Phagocytic properties of microglia in vitro: implications for a role in multiple sclerosis and EAE. Microsc Res Tech 54:81–94

    PubMed  CAS  Google Scholar 

  51. Ji KA, Eu MY, Kang SH, Gwag BJ, Jou I, Joe EH (2008) Differential neutrophil infiltration contributes to regional differences in brain inflammation in the substantia nigra pars compacta and cortex. Glia 56:1039–1047

    PubMed  Google Scholar 

  52. Jana M, Palencia CA, Pahan K (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer’s disease. J Immunol 181:7254–7262

    PubMed  CAS  Google Scholar 

  53. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci 23:7504–7509

    PubMed  CAS  Google Scholar 

  54. Gozes I, Zaltzman R, Hauser J, Brenneman DE, Shohami E, Hill JM (2005) The expression of activity-dependent neuroprotective protein (ADNP) is regulated by brain damage and treatment of mice with the ADNP derived peptide, NAP, reduces the severity of traumatic head injury. Curr Alzheimer Res 2:149–153

    PubMed  CAS  Google Scholar 

  55. Sandhir R, Onyszchuk G, Berman NE (2008) Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp Neurol 213:372–380

    PubMed  CAS  Google Scholar 

  56. Harnett MM (2004) CD40: a growing cytoplasmic tale. Sci STKE 2004:e25

    Google Scholar 

  57. Chen K, Huang J, Gong W, Zhang L, Yu P, Wang JM (2006) CD40/CD40L dyad in the inflammatory and immune responses in the central nervous system. Cell Mol Immunol 3:163–169

    PubMed  CAS  Google Scholar 

  58. Danese S, de la Motte C, Reyes BM, Sans M, Levine AD, Fiocchi C (2004) Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification. J Immunol 172:2011–2015

    PubMed  CAS  Google Scholar 

  59. Tan J, Town T, Mori T et al (2002) CD40 is expressed and functional on neuronal cells. EMBO J 21:643–652

    PubMed  CAS  Google Scholar 

  60. Nguyen VT, Benveniste EN (2000) IL-4-activated STAT-6 inhibits IFN-gamma-induced CD40 gene expression in macrophages/microglia. J Immunol 165:6235–6243

    PubMed  CAS  Google Scholar 

  61. Qin H, Wilson CA, Lee SJ, Zhao X, Benveniste EN (2005) LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia. Blood 106:3114–3122

    PubMed  CAS  Google Scholar 

  62. Calingasan NY, Erdely HA, Altar CA (2002) Identification of CD40 ligand in Alzheimer’s disease and in animal models of Alzheimer’s disease and brain injury. Neurobiol Aging 23:31–39

    PubMed  CAS  Google Scholar 

  63. Gerritse K, Laman JD, Noelle RJ, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E (1996) CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A 93:2499–2504

    PubMed  CAS  Google Scholar 

  64. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314

    PubMed  CAS  Google Scholar 

  65. Kasama T, Strieter RM, Lukacs NW, Burdick MD, Kunkel SL (1994) Regulation of neutrophil-derived chemokine expression by IL-10. J Immunol 152:3559–3569

    PubMed  CAS  Google Scholar 

  66. Lub M, van Kooyk Y, van Vliet SJ, Figdor CG (1997) Dual role of the actin cytoskeleton in regulating cell adhesion mediated by the integrin lymphocyte function-associated molecule-1. Mol Biol Cell 8:341–351

    PubMed  CAS  Google Scholar 

  67. Meagher L, Mahiouz D, Sugars K, Burrows N, Norris P, Yarwood H, Becker-Andre M, Haskard DO (1994) Measurement of mRNA for E-selectin, VCAM-1 and ICAM-1 by reverse transcription and the polymerase chain reaction. J Immunol Methods 175:237–246

    PubMed  CAS  Google Scholar 

  68. Dunehoo AL, Anderson M, Majumdar S, Kobayashi N, Berkland C, Siahaan TJ (2006) Cell adhesion molecules for targeted drug delivery. J Pharm Sci 95:1856–1872

    PubMed  CAS  Google Scholar 

  69. Marlin SD, Springer TA (1987) Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51:813–819

    PubMed  CAS  Google Scholar 

  70. Corti R, Hutter R, Badimon JJ, Fuster V (2004) Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis. J Thromb Thrombolysis 17:35–44

    PubMed  CAS  Google Scholar 

  71. Zameer A, Hoffman SA (2003) Increased ICAM-1 and VCAM-1 expression in the brains of autoimmune mice. J Neuroimmunol 142:67–74

    PubMed  CAS  Google Scholar 

  72. Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127–136

    PubMed  CAS  Google Scholar 

  73. Kyrkanides S, O’Banion MK, Whiteley PE, Daeschner JC, Olschowka JA (2001) Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury. J Neuroimmunol 119:269–277

    PubMed  CAS  Google Scholar 

  74. 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 224:855–862

    PubMed  CAS  Google Scholar 

  75. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 57:1–9

    PubMed  CAS  Google Scholar 

  76. Kanazawa H, Ohsawa K, Sasaki Y, Kohsaka S, Imai Y (2002) Macrophage/microglia-specific protein Iba1 enhances membrane ruffling and Rac activation via phospholipase C-gamma -dependent pathway. J Biol Chem 277:20026–20032

    PubMed  CAS  Google Scholar 

  77. Moynagh PN (2005) The interleukin-1 signalling pathway in astrocytes: a key contributor to inflammation in the brain. J Anat 207:265–269

    PubMed  CAS  Google Scholar 

  78. Neumann H (2001) Control of glial immune function by neurons. Glia 36:191–199

    PubMed  CAS  Google Scholar 

  79. Griffin WS, Sheng JG, Gentleman SM, Graham DI, Mrak RE, Roberts GW (1994) Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression. Neurosci Lett 176:133–136

    PubMed  CAS  Google Scholar 

  80. Griffin WS, Sheng JG, Roberts GW, Mrak RE (1995) Interleukin-1 expression in different plaque types in Alzheimer’s disease: significance in plaque evolution. J Neuropathol Exp Neurol 54:276–281

    PubMed  CAS  Google Scholar 

  81. McGeer PL, Yasojima K, McGeer EG (2002) Association of interleukin-1 beta polymorphisms with idiopathic Parkinson’s disease. Neurosci Lett 326:67–69

    PubMed  CAS  Google Scholar 

  82. Basu A, Krady JK, O’Malley M, Styren SD, DeKosky ST, Levison SW (2002) The type 1 interleukin-1 receptor is essential for the efficient activation of microglia and the induction of multiple proinflammatory mediators in response to brain injury. J Neurosci 22:6071–6082

    PubMed  CAS  Google Scholar 

  83. Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm 70(Suppl):373–381

    CAS  Google Scholar 

  84. Sheng JG, Boop FA, Mrak RE, Griffin WS (1994) Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1 alpha immunoreactivity. J Neurochem 63:1872–1879

    PubMed  CAS  Google Scholar 

  85. Sinha S, Patil SA, Jayalekshmy V, Satishchandra P (2008) Do cytokines have any role in epilepsy? Epilepsy Res 82:171–176

    PubMed  CAS  Google Scholar 

  86. Touzani O, Boutin H, Chuquet J, Rothwell N (1999) Potential mechanisms of interleukin-1 involvement in cerebral ischaemia. J Neuroimmunol 100:203–215

    PubMed  CAS  Google Scholar 

  87. Yamada Y, Ichihara S, Nishida T (2008) Proinflammatory gene polymorphisms and ischemic stroke. Curr Pharm Des 14:3590–3600

    PubMed  CAS  Google Scholar 

  88. Hung CH, Lee CM, Chen CH, Hu TH, Jiang SR, Wang JH, Lu SN, Wang PW (2009) Association of inflammatory and anti-inflammatory cytokines with insulin resistance in chronic hepatitis C. Liver Int (in press)

  89. Stanley LC, Mrak RE, Woody RC, Perrot LJ, Zhang S, Marshak DR, Nelson SJ, Griffin WS (1994) Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer’s disease. J Neuropathol Exp Neurol 53:231–238

    PubMed  CAS  Google Scholar 

  90. Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M (1999) Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 154:1673–1684

    PubMed  CAS  Google Scholar 

  91. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    PubMed  CAS  Google Scholar 

  92. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86:7611–7615

    PubMed  CAS  Google Scholar 

  93. Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer’s disease. Neurobiol Aging 22:903–908

    PubMed  CAS  Google Scholar 

  94. Baranowska-Bik A, Bik W, Wolinska-Witort E, Martynska L, Chmielowska M, Barcikowska M, Baranowska B (2008) Plasma beta amyloid and cytokine profile in women with Alzheimer’s disease. Neuro Endocrinol Lett 29:75–79

    PubMed  CAS  Google Scholar 

  95. Guerreiro RJ, Santana I, Bras JM, Santiago B, Paiva A, Oliveira C (2007) Peripheral inflammatory cytokines as biomarkers in Alzheimer’s disease and mild cognitive impairment. Neurodegener Dis 4:406–412

    PubMed  CAS  Google Scholar 

  96. Forloni G, Demicheli F, Giorgi S, Bendotti C, Angeretti N (1992) Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1. Brain Res Mol Brain Res 16:128–134

    PubMed  CAS  Google Scholar 

  97. Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci USA 89:10075–10078

    PubMed  CAS  Google Scholar 

  98. Gasic-Milenkovic J, Dukic-Stefanovic S, Deuther-Conrad W, Gartner U, Munch G (2003) Beta-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon-gamma and ‘advanced glycation end products’ in a murine microglia cell line. Eur J NeuroSci 17:813–821

    PubMed  Google Scholar 

  99. Chauhan NB, Siegel GJ, Lichtor T (2004) Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-Abeta antibody into the third ventricle of TgCRND8 mice. J Neurosci Res 78:732–741

    PubMed  CAS  Google Scholar 

  100. Clarke RM, O’Connell F, Lyons A, Lynch MA (2007) The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-beta1-42 in the rat hippocampus in vivo. Neuropharmacology 52:136–145

    PubMed  CAS  Google Scholar 

  101. Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152:307–317

    PubMed  CAS  Google Scholar 

  102. Piazza A, Lynch MA (2009) Neuroinflammatory changes increase the impact of stressors on neuronal function. Biochem Soc Trans 37:303–307

    PubMed  CAS  Google Scholar 

  103. Gadient RA, Cron KC, Otten U (1990) Interleukin-1 beta and tumor necrosis factor-alpha synergistically stimulate nerve growth factor (NGF) release from cultured rat astrocytes. Neurosci Lett 117:335–340

    PubMed  CAS  Google Scholar 

  104. Juric DM, Carman-Krzan M (2001) Interleukin-1 beta, but not IL-1 alpha, mediates nerve growth factor secretion from rat astrocytes via type I IL-1 receptor. Int J Dev Neurosci 19:675–683

    PubMed  CAS  Google Scholar 

  105. Ling ZD, Potter ED, Lipton JW, Carvey PM (1998) Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 149:411–423

    PubMed  CAS  Google Scholar 

  106. Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O’Banion MK (2007) Sustained hippocampal IL-1beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 117:1595–1604

    PubMed  CAS  Google Scholar 

  107. Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, Yirmiya R (2003) Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 13:826–834

    PubMed  CAS  Google Scholar 

  108. Miller RJ, Rostene W, Apartis E, Banisadr G, Biber K, Milligan ED, White FA, Zhang J (2008) Chemokine action in the nervous system. J Neurosci 28:11792–11795

    PubMed  CAS  Google Scholar 

  109. Kurihara T, Warr G, Loy J, Bravo R (1997) Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J Exp Med 186:1757–1762

    PubMed  CAS  Google Scholar 

  110. Kuziel WA, Morgan SJ, Dawson TC, Griffin S, Smithies O, Ley K, Maeda N (1997) Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A 94:12053–12058

    PubMed  CAS  Google Scholar 

  111. Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, North R, Gerard C, Rollins BJ (1998) Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 187:601–608

    PubMed  CAS  Google Scholar 

  112. Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Lancero M, Narvaez A, McGrath MS (2006) MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 179:87–93

    PubMed  CAS  Google Scholar 

  113. Mennicken F, Maki R, de Souza EB, Quirion R (1999) Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol Sci 20:73–78

    PubMed  CAS  Google Scholar 

  114. Rankine EL, Hughes PM, Botham MS, Perry VH, Felton LM (2006) Brain cytokine synthesis induced by an intraparenchymal injection of LPS is reduced in MCP-1-deficient mice prior to leucocyte recruitment. Eur J NeuroSci 24:77–86

    PubMed  CAS  Google Scholar 

  115. Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C (2002) Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 22:308–317

    PubMed  CAS  Google Scholar 

  116. Felton LM, Cunningham C, Rankine EL, Waters S, Boche D, Perry VH (2005) MCP-1 and murine prion disease: separation of early behavioural dysfunction from overt clinical disease. Neurobiol Dis 20:283–295

    PubMed  CAS  Google Scholar 

  117. Cota M, Kleinschmidt A, Ceccherini-Silberstein F, Aloisi F, Mengozzi M, Mantovani A, Brack-Werner R, Poli G (2000) Upregulated expression of interleukin-8, RANTES and chemokine receptors in human astrocytic cells infected with HIV-1. J Neurovirol 6:75–83

    PubMed  CAS  Google Scholar 

  118. Little AR, Benkovic SA, Miller DB, O’Callaghan JP (2002) Chemically induced neuronal damage and gliosis: enhanced expression of the proinflammatory chemokine, monocyte chemoattractant protein (MCP)-1, without a corresponding increase in proinflammatory cytokines(1). Neuroscience 115:307–320

    PubMed  CAS  Google Scholar 

  119. Hayashi M, Luo Y, Laning J, Strieter RM, Dorf ME (1995) Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol 60:143–150

    PubMed  CAS  Google Scholar 

  120. Aloisi F, De Simone R, Columba-Cabezas S, Penna G, Adorini L (2000) Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells. J Immunol 164:1705–1712

    PubMed  CAS  Google Scholar 

  121. Cowell RM, Xu H, Galasso JM, Silverstein FS (2002) Hypoxic-ischemic injury induces macrophage inflammatory protein-1alpha expression in immature rat brain. Stroke 33:795–801

    PubMed  CAS  Google Scholar 

  122. Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD (1995) An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 155:5003–5010

    PubMed  CAS  Google Scholar 

  123. Miyagishi R, Kikuchi S, Fukazawa T, Tashiro K (1995) Macrophage inflammatory protein-1 alpha in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. J Neurol Sci 129:223–227

    PubMed  CAS  Google Scholar 

  124. Ren LQ, Gourmala N, Boddeke HW, Gebicke-Haerter PJ (1998) Lipopolysaccharide-induced expression of IP-10 mRNA in rat brain and in cultured rat astrocytes and microglia. Brain Res Mol Brain Res 59:256–263

    PubMed  CAS  Google Scholar 

  125. Duan RS, Yang X, Chen ZG, Lu MO, Morris C, Winblad B, Zhu J (2008) Decreased fractalkine and increased IP-10 expression in aged brain of APP(swe) transgenic mice. Neurochem Res 33:1085–1089

    PubMed  CAS  Google Scholar 

  126. Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Venturelli E, Pijnenburg YA, Bresolin N, Scarpini E (2006) Intrathecal chemokine levels in Alzheimer disease and frontotemporal lobar degeneration. Neurology 66:146–147

    PubMed  CAS  Google Scholar 

  127. Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT (2000) Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol 108:227–235

    PubMed  CAS  Google Scholar 

  128. Gunn MD, Nelken NA, Liao X, Williams LT (1997) Monocyte chemoattractant protein-1 is sufficient for the chemotaxis of monocytes and lymphocytes in transgenic mice but requires an additional stimulus for inflammatory activation. J Immunol 158:376–383

    PubMed  CAS  Google Scholar 

  129. D’Andrea MR, Cole GM, Ard MD (2004) The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging 25:675–683

    PubMed  Google Scholar 

  130. El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432–438

    PubMed  CAS  Google Scholar 

  131. Jimenez S, Baglietto-Vargas D, Caballero C et al (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 28:11650–11661

    PubMed  CAS  Google Scholar 

  132. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49:489–502

    PubMed  CAS  Google Scholar 

  133. Mackenzie IR, Hao C, Munoz DG (1995) Role of microglia in senile plaque formation. Neurobiol Aging 16:797–804

    PubMed  CAS  Google Scholar 

  134. Sheng JG, Mrak RE, Griffin WS (1997) Neuritic plaque evolution in Alzheimer’s disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms. Acta Neuropathol (Berl) 94:1–5

    CAS  Google Scholar 

  135. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14:681–687

    PubMed  CAS  Google Scholar 

  136. Jucker M, Heppner FL (2008) Cerebral and peripheral amyloid phagocytes—an old liaison with a new twist. Neuron 59:8–10

    PubMed  CAS  Google Scholar 

  137. 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 10:1538–1543

    PubMed  CAS  Google Scholar 

  138. Grathwohl S, Kalin R, Bolmont T, Radde R, Kohsaka S, Wolburg H, Heppner FJ, Jucker M (2008) Microglia ablation does not alter plaque formation and maintenance in a mouse model of cerebral amyloidosis. Alzheimer’s and Dementia 4:T239

  139. Kopec KK, Carroll RT (1998) Alzheimer’s beta-amyloid peptide 1–42 induces a phagocytic response in murine microglia. J Neurochem 71:2123–2131

    Article  PubMed  CAS  Google Scholar 

  140. Paresce DM, Ghosh RN, Maxfield FR (1996) Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 17:553–565

    PubMed  CAS  Google Scholar 

  141. Shaffer LM, Dority MD, Gupta-Bansal R, Frederickson RC, Younkin SG, Brunden KR (1995) Amyloid beta protein (A beta) removal by neuroglial cells in culture. Neurobiol Aging 16:737–745

    PubMed  CAS  Google Scholar 

  142. Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O’Hare E, Esler WP, Maggio JE, Mantyh PW (1998) Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18:2161–2173

    PubMed  CAS  Google Scholar 

  143. Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR (2007) Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell 18:1490–1496

    PubMed  CAS  Google Scholar 

  144. von Bernhardi R, Eugenin J (2004) Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res 1025:186–193

    Google Scholar 

  145. Napoli I, Neumann H (2009) Microglial clearance function in health and disease. Neuroscience 158:1030–1038

    PubMed  CAS  Google Scholar 

  146. Inoue K, Koizumi S, Tsuda M (2007) The role of nucleotides in the neuron–glia communication responsible for the brain functions. J Neurochem 102:1447–1458

    PubMed  CAS  Google Scholar 

  147. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K et al (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446:1091–1095

    PubMed  CAS  Google Scholar 

  148. Rotshenker S, Reichert F, Gitik M, Haklai R, Elad-Sfadia G, Kloog Y (2008) Galectin-3/MAC-2, Ras and PI3K activate complement receptor-3 and scavenger receptor-AI/II mediated myelin phagocytosis in microglia. Glia 56:1607–1613

    PubMed  Google Scholar 

  149. Aravalli RN, Peterson PK, Lokensgard JR (2007) Toll-like receptors in defense and damage of the central nervous system. J Neuroimmune Pharmacol 2:297–312

    PubMed  Google Scholar 

  150. Mishra BB, Gundra UM, Teale JM (2008) Expression and distribution of Toll-like receptors 11–13 in the brain during murine neurocysticercosis. J Neuroinflammation 5:53

    PubMed  Google Scholar 

  151. Mishra BB, Mishra PK, Teale JM (2006) Expression and distribution of Toll-like receptors in the brain during murine neurocysticercosis. J Neuroimmunol 181:46–56

    PubMed  CAS  Google Scholar 

  152. Glezer I, Simard AR, Rivest S (2007) Neuroprotective role of the innate immune system by microglia. Neuroscience 147:867–883

    PubMed  CAS  Google Scholar 

  153. Ribes S, Ebert S, Czesnik D et al (2009) Toll-like receptor prestimulation increases phagocytosis of Escherichia coli DH5alpha and Escherichia coli K1 strains by murine microglial cells. Infect Immun 77:557–564

    PubMed  CAS  Google Scholar 

  154. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129:3006–3019

    PubMed  Google Scholar 

  155. Richard KL, Filali M, Prefontaine P, Rivest S (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. J Neurosci 28:5784–5793

    PubMed  CAS  Google Scholar 

  156. Kong L, Ge BX (2008) MyD88-independent activation of a novel actin-Cdc42/Rac pathway is required for Toll-like receptor-stimulated phagocytosis. Cell Res 18:745–755

    PubMed  CAS  Google Scholar 

  157. Nikolic WV, Hou H, Town T et al (2008) Peripherally administered human umbilical cord blood cells reduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice. Stem Cells Dev 17:423–439

    PubMed  CAS  Google Scholar 

  158. Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M (1999) Microglial activation resulting from CD40–CD40L interaction after beta-amyloid stimulation. Science 286:2352–2355

    PubMed  CAS  Google Scholar 

  159. Grandbarbe L, Michelucci A, Heurtaux T, Hemmer K, Morga E, Heuschling P (2007) Notch signaling modulates the activation of microglial cells. Glia 55:1519–1530

    PubMed  Google Scholar 

  160. Schwab C, McGeer PL (2008) Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis 13:359–369

    PubMed  CAS  Google Scholar 

  161. Piccio L, Buonsanti C, Cella M et al (2008) Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 131:3081–3091

    PubMed  Google Scholar 

  162. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4:e124

    PubMed  Google Scholar 

  163. Neumann H, Takahashi K (2007) Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J Neuroimmunol 184:92–99

    PubMed  CAS  Google Scholar 

  164. Frank S, Burbach GJ, Bonin M, Walter M, Streit W, Bechmann I, Deller T (2008) TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56:1438–1447

    PubMed  Google Scholar 

  165. Lynch AM, Loane DJ, Minogue AM, Clarke RM, Kilroy D, Nally RE, Roche OJ, O’Connell F, Lynch MA (2007) Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging 28:845–855

    PubMed  CAS  Google Scholar 

  166. Hausler KG, Prinz M, Nolte C, Weber JR, Schumann RR, Kettenmann H, Hanisch UK (2002) Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages. Eur J NeuroSci 16:2113–2122

    PubMed  Google Scholar 

  167. Perussia B, Dayton ET, Fanning V, Thiagarajan P, Hoxie J, Trinchieri G (1983) Immune interferon and leukocyte-conditioned medium induce normal and leukemic myeloid cells to differentiate along the monocytic pathway. J Exp Med 158:2058–2080

    PubMed  CAS  Google Scholar 

  168. Blasko I, Ransmayr G, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B (2001) Does IFN gamma play a role in neurodegeneration? J Neuroimmunol 116:1–4

    PubMed  CAS  Google Scholar 

  169. Hallam DM, Capps NL, Travelstead AL, Brewer GJ, Maroun LE (2000) Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis. J Neuroimmunol 110:66–75

    PubMed  CAS  Google Scholar 

  170. Neumann H, Schmidt H, Wilharm E, Behrens L, Wekerle H (1997) Interferon gamma gene expression in sensory neurons: evidence for autocrine gene regulation. J Exp Med 186:2023–2031

    PubMed  CAS  Google Scholar 

  171. Nitta T, Ebato M, Sato K, Okumura K (1994) Expression of tumour necrosis factor-alpha, -beta and interferon-gamma genes within human neuroglial tumour cells and brain specimens. Cytokine 6:171–180

    PubMed  CAS  Google Scholar 

  172. Suzuki Y, Claflin J, Wang X, Lengi A, Kikuchi T (2005) Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol 35:83–90

    PubMed  CAS  Google Scholar 

  173. Clarke RM, Lyons A, O’Connell F, Deighan BF, Barry CE, Anyakoha NG, Nicolaou A, Lynch MA (2008) A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain. J Biol Chem 283:1808–1817

    PubMed  CAS  Google Scholar 

  174. Griffin DE (1997) Cytokines in the brain during viral infection: clues to HIV-associated dementia. J Clin Invest 100:2948–2951

    PubMed  CAS  Google Scholar 

  175. Shaftel SS, Carlson TJ, Olschowka JA, Kyrkanides S, Matousek SB, O’Banion MK (2007) Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci 27:9301–9309

    PubMed  CAS  Google Scholar 

  176. Bake S, Sohrabji F (2004) 17beta-estradiol differentially regulates blood-brain barrier permeability in young and aging female rats. Endocrinology 145:5471–5475

    PubMed  CAS  Google Scholar 

  177. Ujiie M, Dickstein DL, Carlow DA, Jefferies WA (2003) Blood–brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10:463–470

    PubMed  CAS  Google Scholar 

  178. Hafezi-Moghadam A, Thomas KL, Wagner DD (2006) ApoE-deficiency leads to a progressive age-dependent blood brain barrier leakage. Am J Physiol Cell Physiol 292:C1256–C1262

    PubMed  Google Scholar 

  179. Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B (1999) TNF alpha plus IFN gamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J 13:63–68

    PubMed  CAS  Google Scholar 

  180. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B (2000) Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1–40 and Abeta1–42 by human astrocytes. Neurobiol Dis 7:682–689

    PubMed  CAS  Google Scholar 

  181. Klegeris A, Walker DG, McGeer PL (1994) Activation of macrophages by Alzheimer beta amyloid peptide. Biochem Biophys Res Commun 199:984–991

    PubMed  CAS  Google Scholar 

  182. 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 27:8309–8313

    PubMed  CAS  Google Scholar 

  183. Fiala M, Zhang L, Gan X et al (1998) Amyloid-beta induces chemokine secretion and monocyte migration across a human blood–brain barrier model. Mol Med 4:480–489

    PubMed  CAS  Google Scholar 

  184. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647–650

    PubMed  CAS  Google Scholar 

  185. Yates SL, Burgess LH, Kocsis-Angle J, Antal JM, Dority MD, Embury PB, Piotrkowski AM, Brunden KR (2000) Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia. J Neurochem 74:1017–1025

    PubMed  CAS  Google Scholar 

  186. Farber K, Kettenmann H (2006) Purinergic signaling and microglia. Pflugers Arch 452:615–621

    PubMed  Google Scholar 

  187. Minghetti L (2005) Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 18:315–321

    PubMed  CAS  Google Scholar 

  188. Okura Y, Kohyama K, Park IK, Matsumoto Y (2008) Nonviral DNA vaccination augments microglial phagocytosis of beta-amyloid deposits as a major clearance pathway in an Alzheimer disease mouse model. J Neuropathol Exp Neurol 67:1063–1071

    PubMed  CAS  Google Scholar 

  189. Yan SD, Chen X, Fu J et al (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691

    PubMed  CAS  Google Scholar 

  190. Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23:2665–2674

    PubMed  CAS  Google Scholar 

  191. El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382:716–719

    PubMed  CAS  Google Scholar 

  192. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T (2009) Inflammation in Alzheimer’s disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 87:181–194

    PubMed  CAS  Google Scholar 

  193. Donahue JE, Flaherty SL, Johanson CE et al (2006) RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol 112:405–415

    PubMed  CAS  Google Scholar 

  194. Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB (2000) beta-Amyloid(1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632

    PubMed  CAS  Google Scholar 

  195. Sloane JA, Hollander W, Moss MB, Rosene DL, Abraham CR (1999) Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol Aging 20:395–405

    PubMed  CAS  Google Scholar 

  196. Hauss-Wegrzyniak B, Vraniak P, Wenk GL (1999) The effects of a novel NSAID on chronic neuroinflammation are age dependent. Neurobiol Aging 20:305–313

    PubMed  CAS  Google Scholar 

  197. Kullberg S, Aldskogius H, Ulfhake B (2001) Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord. Brain Res 899:169–186

    PubMed  CAS  Google Scholar 

  198. Rozovsky I, Finch CE, Morgan TE (1998) Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. Neurobiol Aging 19:97–103

    PubMed  CAS  Google Scholar 

  199. Downer EJ, Cowley TR, Lyons A, Mills KH, Berezin V, Bock E, Lynch MA (2008) A novel anti-inflammatory role of NCAM-derived mimetic peptide, FGL. Neurobiol Aging (in press) doi:10.1016/j.neurobiolaging.2008.03.017

  200. 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 19:1329–1331

    PubMed  CAS  Google Scholar 

  201. Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65:199–203

    PubMed  Google Scholar 

  202. Sheng JG, Griffin WS, Royston MC, Mrak RE (1998) Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer’s disease. Neuropathol Appl Neurobiol 24:278–283

    PubMed  CAS  Google Scholar 

  203. Baune BT, Ponath G, Rothermundt M, Roesler A, Berger K (2009) Association between cytokines and cerebral MRI changes in the aging brain. J Geriatr Psychiatry Neurol 22:23–34

    PubMed  Google Scholar 

  204. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167

    PubMed  CAS  Google Scholar 

  205. Godbout JP, Johnson RW (2004) Interleukin-6 in the aging brain. J Neuroimmunol 147:141–144

    PubMed  CAS  Google Scholar 

  206. Gelinas DS, McLaurin J (2005) PPAR-alpha expression inversely correlates with inflammatory cytokines IL-1beta and TNF-alpha in aging rats. Neurochem Res 30:1369–1375

    PubMed  CAS  Google Scholar 

  207. Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y (2000) Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885:25–31

    PubMed  CAS  Google Scholar 

  208. Rowe WB, Blalock EM, Chen KC et al (2007) Hippocampal expression analyses reveal selective association of immediate–early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats. J Neurosci 27:3098–3110

    PubMed  CAS  Google Scholar 

  209. Maher FO, Nolan Y, Lynch MA (2005) Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat. Neurobiol Aging 26:717–728

    PubMed  CAS  Google Scholar 

  210. Ye SM, Johnson RW (1999) Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 93:139–148

    PubMed  CAS  Google Scholar 

  211. Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9:183–192

    PubMed  CAS  Google Scholar 

  212. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW (2001) Interleukin-10 in the brain. Crit Rev Immunol 21:427–449

    PubMed  CAS  Google Scholar 

  213. Loane DJ, Deighan BF, Clarke RM, Griffin RJ, Lynch AM, Lynch MA (2007) Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain. Neurobiol Aging 30:920–931

    PubMed  Google Scholar 

  214. Barclay AN, Wright GJ, Brooke G, Brown MH (2002) CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23:285–290

    PubMed  CAS  Google Scholar 

  215. Jenmalm MC, Cherwinski H, Bowman EP, Phillips JH, Sedgwick JD (2006) Regulation of myeloid cell function through the CD200 receptor. J Immunol 176:191–199

    PubMed  CAS  Google Scholar 

  216. Hoek RM, Ruuls SR, Murphy CA et al (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771

    PubMed  CAS  Google Scholar 

  217. Broderick C, Hoek RM, Forrester JV, Liversidge J, Sedgwick JD, Dick AD (2002) Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am J Pathol 161:1669–1677

    PubMed  CAS  Google Scholar 

  218. Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Takahashi H, Imai Y, Tanaka J (2007) Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion. Neurosci Lett 418:44–48

    PubMed  CAS  Google Scholar 

  219. Walker DG, Dalsing-Hernandez JE, Campbell NA, Lue LF (2009) Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation. Exp Neurol 215:5–19

    PubMed  CAS  Google Scholar 

  220. Lyons A, Downer E, Molloy B, Lynch MA (2008) Interaction of glia with other cell types regulates their activation state. FENS Abstr. 4, A152.25

  221. Lyons A, Lynch AM, Downer E, 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. doi:10.1111/j.1471-4159.2009.06253.x

  222. Harrison JK, Jiang Y, Chen S et al (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 95:10896–10901

    PubMed  CAS  Google Scholar 

  223. Maciejewski-Lenoir D, Chen S, Feng L, Maki R, Bacon KB (1999) Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia. J Immunol 163:1628–1635

    PubMed  CAS  Google Scholar 

  224. Zujovic V, Benavides J, Vige X, Carter C, Taupin V (2000) Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 29:305–315

    PubMed  CAS  Google Scholar 

  225. Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924

    PubMed  CAS  Google Scholar 

  226. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145

    PubMed  CAS  Google Scholar 

  227. Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86:342–367

    PubMed  CAS  Google Scholar 

  228. Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206

    PubMed  CAS  Google Scholar 

  229. Aloisi F, Penna G, Cerase J, Menendez Iglesias B, Adorini L (1997) IL-12 production by central nervous system microglia is inhibited by astrocytes. J Immunol 159:1604–1612

    PubMed  CAS  Google Scholar 

  230. Vincent VA, Van Dam AM, Persoons JH, Schotanus K, Steinbusch HW, Schoffelmeer AN, Berkenbosch F (1996) Gradual inhibition of inducible nitric oxide synthase but not of interleukin-1 beta production in rat microglial cells of endotoxin-treated mixed glial cell cultures. Glia 17:94–102

    PubMed  CAS  Google Scholar 

  231. Min KJ, Yang MS, Kim SU, Jou I, Joe EH (2006) Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J Neurosci 26:1880–1887

    PubMed  CAS  Google Scholar 

  232. Vincent VA, Tilders FJ, Van Dam AM (1997) Inhibition of endotoxin-induced nitric oxide synthase production in microglial cells by the presence of astroglial cells: a role for transforming growth factor beta. Glia 19:190–198

    PubMed  CAS  Google Scholar 

  233. Wang T, Gong N, Liu J, Kadiu I, Kraft-Terry SD, Mosley RL, Volsky DJ, Ciborowski P, Gendelman HE (2008) Proteomic modeling for HIV-1 infected microglia–astrocyte crosstalk. PLoS ONE 3:e2507

    PubMed  Google Scholar 

  234. Seguin R, Biernacki K, Prat A, Wosik K, Kim HJ, Blain M, McCrea E, Bar-Or A, Antel JP (2003) Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia. Glia 42:36–45

    PubMed  Google Scholar 

  235. Chabot S, Charlet D, Wilson TL, Yong VW (2001) Cytokine production consequent to T cell–microglia interaction: the PMA/IFN gamma-treated U937 cells display similarities to human microglia. J Neurosci Methods 105:111–120

    PubMed  CAS  Google Scholar 

  236. Giuliani F, Hader W, Yong VW (2005) Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell–microglia interaction. J Leukoc Biol 78:135–143

    PubMed  CAS  Google Scholar 

  237. Cannella B, Aquino DA, Raine CS (1995) MHC II expression in the CNS after long-term demyelination. J Neuropathol Exp Neurol 54:521–530

    PubMed  CAS  Google Scholar 

  238. Cannella B, Raine CS (1995) The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37:424–435

    PubMed  CAS  Google Scholar 

  239. Familian A, Eikelenboom P, Veerhuis R (2007) Minocycline does not affect amyloid beta phagocytosis by human microglial cells. Neurosci Lett 416:87–91

    PubMed  CAS  Google Scholar 

  240. Streit WJ (2006) Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 29:506–510

    PubMed  CAS  Google Scholar 

  241. Wilcock DM, Rojiani A, Rosenthal A et al (2004) Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci 24:6144–6151

    PubMed  CAS  Google Scholar 

  242. Morgan SC, Taylor DL, Pocock JM (2004) Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades. J Neurochem 90:89–101

    PubMed  CAS  Google Scholar 

  243. Polazzi E, Gianni T, Contestabile A (2001) Microglial cells protect cerebellar granule neurons from apoptosis: evidence for reciprocal signaling. Glia 36:271–280

    PubMed  CAS  Google Scholar 

  244. De Simone R, Ajmone-Cat MA, Tirassa P, Minghetti L (2003) Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells. J Neuropathol Exp Neurol 62:208–216

    PubMed  Google Scholar 

  245. Minghetti L, Ajmone-Cat MA, De Berardinis MA, De Simone R (2005) Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Brain Res Rev 48:251–256

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marina A. Lynch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lynch, M.A. The Multifaceted Profile of Activated Microglia. Mol Neurobiol 40, 139–156 (2009). https://doi.org/10.1007/s12035-009-8077-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-009-8077-9

Keywords

Navigation