Advertisement

Seminars in Immunopathology

, Volume 31, Issue 4, pp 513–525 | Cite as

Role of microglia in neuronal degeneration and regeneration

  • Lisa Walter
  • Harald Neumann
Review

Abstract

Microglial cells, the resident macrophage population of the central nervous system (CNS), actively scan tissue under both normal and pathologic contexts. Their resulting engagement can become either neuroprotective or neurotoxic, leading to amelioration or aggravation of disease progression. In this review, we focus on the molecular signaling molecules involved in microglial responses and discuss observations demonstrating the diverse effects of microglia in animal models of CNS diseases.

Keywords

Microglia Neuroinflammation Neurodegeneration Neural regeneration 

Notes

Acknowledgments

The Neural Regeneration Group at the University Bonn is supported by the Hertie-Foundation, the Walter-und-Ilse-Rose-Foundation, the DFG (SFB704, KFO177), and the EU (LSHM-CT-2005-018637).

Conflict of interest statement

The authors declare that they have no competing financial interest.

References

  1. 1.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev, Neurosci 8:57–69CrossRefGoogle Scholar
  2. 2.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedCrossRefGoogle Scholar
  3. 3.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedCrossRefGoogle Scholar
  4. 4.
    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
  5. 5.
    Fetler L, Amigorena S (2005) Neuroscience. Brain under surveillance: the microglia patrol. Science 309:392–393PubMedCrossRefGoogle Scholar
  6. 6.
    Raivich G (2005) Like cops on the beat: the active role of resting microglia. Trends Neurosci 28:571–573PubMedCrossRefGoogle Scholar
  7. 7.
    Oehmichen W, Gencic M (1975) Experimental studies on kinetics and functions of monuclear phagozytes of the central nervous system. Acta Neuropathol Suppl (Suppl 6):285–290Google Scholar
  8. 8.
    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 53:92–102PubMedCrossRefGoogle Scholar
  9. 9.
    Neumann H (2001) Control of glial immune function by neurons. Glia 36:191–199PubMedCrossRefGoogle Scholar
  10. 10.
    Harry GJ, McPherson CA, Wine RN, Atkinson K, Lefebvre d'Hellencourt C (2004) Trimethyltin-induced neurogenesis in the murine hippocampus. Neurotox Res 5:623–627PubMedCrossRefGoogle Scholar
  11. 11.
    Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139PubMedCrossRefGoogle Scholar
  12. 12.
    Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS (2002) Role of nitric oxide in inflammation-mediated neurodegeneration. Ann N Y Acad Sci 962:318–331PubMedCrossRefGoogle Scholar
  13. 13.
    Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP 2nd, Scheffler B, Steindler DA (2006) Microglia instruct subventricular zone neurogenesis. Glia 54:815–825PubMedCrossRefGoogle Scholar
  14. 14.
    Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275PubMedCrossRefGoogle Scholar
  15. 15.
    Colton CA, Gilbert DL (1987) Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 223:284–288PubMedCrossRefGoogle Scholar
  16. 16.
    Sawada M, Kondo N, Suzumura A, Marunouchi T (1989) Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res 491:394–397PubMedCrossRefGoogle Scholar
  17. 17.
    Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW (1993) Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol 150:2659–2667PubMedGoogle Scholar
  18. 18.
    Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980PubMedCrossRefGoogle Scholar
  19. 19.
    Sawada M, Sawada H, Nagatsu T (2008) Effects of aging on neuroprotective and neurotoxic properties of microglia in neurodegenerative diseases. Neurodegener Dis 5:254–256PubMedCrossRefGoogle Scholar
  20. 20.
    Gensel JC, Nakamura S, Guan Z, van Rooijen N, Ankeny DP, Popovich PG (2009) Macrophages promote axon regeneration with concurrent neurotoxicity. J Neurosci 29:3956–3968PubMedCrossRefGoogle Scholar
  21. 21.
    Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146–152PubMedCrossRefGoogle Scholar
  22. 22.
    Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451:720–724PubMedCrossRefGoogle Scholar
  23. 23.
    Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28:4283–4292PubMedCrossRefGoogle Scholar
  24. 24.
    Kress H, Stelzer EH, Holzer D, Buss F, Griffiths G, Rohrbach A (2007) Filopodia act as phagocytic tentacles and pull with discrete steps and a load-dependent velocity. Proc Natl Acad Sci U S A 104:11633–11638PubMedCrossRefGoogle Scholar
  25. 25.
    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
  26. 26.
    Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C, Kovac AD, Gerard C, Boddeke HW, Nitsch R, Kettenmann H (2004) CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci 24:8500–8509PubMedCrossRefGoogle Scholar
  27. 27.
    Biber K, Neumann H, Inoue K, Boddeke HW (2007) Neuronal ‘on’ and ‘off’ signals control microglia. Trends Neurosci 30:596–602PubMedCrossRefGoogle Scholar
  28. 28.
    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
  29. 29.
    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 13:432–438PubMedCrossRefGoogle Scholar
  30. 30.
    van der Laan LJ, Ruuls SR, Weber KS, Lodder IJ, Dopp EA, Dijkstra CD (1996) Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor-alpha and nitric oxide. J Neuroimmunol 70:145–152PubMedCrossRefGoogle Scholar
  31. 31.
    Bullard DC, Hu X, Schoeb TR, Axtell RC, Raman C, Barnum SR (2005) Critical requirement of CD11b (Mac-1) on T cells and accessory cells for development of experimental autoimmune encephalomyelitis. J Immunol 175:6327–6333PubMedGoogle Scholar
  32. 32.
    Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K (2007) The fibrin-derived gamma377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 204:571–582PubMedCrossRefGoogle Scholar
  33. 33.
    Martin DE, Chiu FJ, Gigli I, Muller-Eberhard HJ (1987) Killing of human melanoma cells by the membrane attack complex of human complement as a function of its molecular composition. J Clin Invest 80:226–233PubMedCrossRefGoogle Scholar
  34. 34.
    Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, Dinkel K (2006) Microglia provide neuroprotection after ischemia. FASEB J 20:714–716PubMedGoogle Scholar
  35. 35.
    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
  36. 36.
    Franklin RJM, Kotter MR (2008) The biology of CNS remyelination: the key to therapeutic advances. J Neurol 255(Suppl 1):19–25PubMedCrossRefGoogle Scholar
  37. 37.
    Dubois-Dalcq M, Ffrench-Constant C, Franklin RJM (2005) Enhancing central nervous system remyelination in multiple sclerosis. Neuron 48:9–12PubMedCrossRefGoogle Scholar
  38. 38.
    Kotter MR, Li WW, Zhao C, Franklin RJM (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332PubMedCrossRefGoogle Scholar
  39. 39.
    Kotter MR, Zhao C, van Rooijen N, Franklin RJM (2005) Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 18:166–175PubMedCrossRefGoogle Scholar
  40. 40.
    Ravichandran KS (2003) “Recruitment signals” from apoptotic cells: invitation to a quiet meal. Cell 113:817–820PubMedCrossRefGoogle Scholar
  41. 41.
    Ravichandran KS, Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev, Immunol 7:964–974CrossRefGoogle Scholar
  42. 42.
    Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439PubMedCrossRefGoogle Scholar
  43. 43.
    Kobayashi N, Karisola P, Pena-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927–940PubMedCrossRefGoogle Scholar
  44. 44.
    Santiago C, Ballesteros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM (2007) Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27:941–951PubMedCrossRefGoogle Scholar
  45. 45.
    Santiago C, Ballesteros A, Tami C, Martinez-Munoz L, Kaplan GG, Casasnovas JM (2007) Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity 26:299–310PubMedCrossRefGoogle Scholar
  46. 46.
    Park D, Hochreiter-Hufford A, Ravichandran KS (2009) The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr Biol 19:346–351PubMedCrossRefGoogle Scholar
  47. 47.
    Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–434PubMedCrossRefGoogle Scholar
  48. 48.
    Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY, Lee BH, Kwon TH, Park RW, Kim IS (2008) Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ 15:192–201PubMedCrossRefGoogle Scholar
  49. 49.
    Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187PubMedCrossRefGoogle Scholar
  50. 50.
    Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150PubMedCrossRefGoogle Scholar
  51. 51.
    Ishimoto Y, Ohashi K, Mizuno K, Nakano T (2000) Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. J Biochem 127:411–417PubMedGoogle Scholar
  52. 52.
    Grommes C, Lee CY, Wilkinson BL, Jiang Q, Koenigsknecht-Talboo JL, Varnum B, Landreth GE (2008) Regulation of microglial phagocytosis and inflammatory gene expression by Gas6 acting on the Axl/Mer family of tyrosine kinases. J Neuroimmune Pharmacol 3:130–140PubMedCrossRefGoogle Scholar
  53. 53.
    Paidassi H, Tacnet-Delorme P, Garlatti V, Darnault C, Ghebrehiwet B, Gaboriaud C, Arlaud GJ, Frachet P (2008) C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J Immunol 180:2329–2338PubMedGoogle Scholar
  54. 54.
    Goldstein JL, Brown MS, Krieger M, Anderson RG, Mintz B (1979) Demonstration of low density lipoprotein receptors in mouse teratocarcinoma stem cells and description of a method for producing receptor-deficient mutant mice. Proc Natl Acad Sci U S A 76:2843–2847PubMedCrossRefGoogle Scholar
  55. 55.
    Husemann J, Loike JD, Anankov R, Febbraio M, Silverstein SC (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40:195–205PubMedCrossRefGoogle Scholar
  56. 56.
    Husemann J, Silverstein SC (2001) Expression of scavenger receptor class B, type I, by astrocytes and vascular smooth muscle cells in normal adult mouse and human brain and in Alzheimer's disease brain. Am J Pathol 158:825–832PubMedGoogle Scholar
  57. 57.
    Christie RH, Freeman M, Hyman BT (1996) Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer's disease. Am J Pathol 148:399–403PubMedGoogle Scholar
  58. 58.
    Paresce DM, Ghosh RN, Maxfield FR (1996) Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 17:553–565PubMedCrossRefGoogle Scholar
  59. 59.
    Kraal G, van der Laan LJ, Elomaa O, Tryggvason K (2000) The macrophage receptor MARCO. Microbes Infect 2:313–316PubMedCrossRefGoogle Scholar
  60. 60.
    Alarcon R, Fuenzalida C, Santibanez M, von Bernhardi R (2005) Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound beta-amyloid. J Biol Chem 280:30406–30415PubMedCrossRefGoogle Scholar
  61. 61.
    Zhou Z, Hartwieg E, Horvitz HR (2001) CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104:43–56PubMedCrossRefGoogle Scholar
  62. 62.
    Ziegenfuss JS, Biswas R, Avery MA, Hong K, Sheehan AE, Yeung YG, Stanley ER, Freeman MR (2008) Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature 453:935–939PubMedCrossRefGoogle Scholar
  63. 63.
    McVicar DW, Taylor LS, Gosselin P, Willette-Brown J, Mikhael AI, Geahlen RL, Nakamura MC, Linnemeyer P, Seaman WE, Anderson SK, Ortaldo JR, Mason LH (1998) DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase. J Biol Chem 273:32934–32942PubMedCrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647–657PubMedCrossRefGoogle Scholar
  66. 66.
    Quan DN, Cooper MD, Potter JL, Roberts MH, Cheng H, Jarvis GA (2008) TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells. Mucosal Immunol 1:229–238PubMedCrossRefGoogle Scholar
  67. 67.
    N'Diaye EN, Branda CS, Branda SS, Nevarez L, Colonna M, Lowell C, Hamerman JA, Seaman WE (2009) TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol 184:215–223PubMedCrossRefGoogle Scholar
  68. 68.
    Hsieh CL, Koike M, Spusta S, Niemi E, 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
  69. 69.
    Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T, Peltonen L (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25:357–361PubMedCrossRefGoogle Scholar
  70. 70.
    Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656–662PubMedCrossRefGoogle Scholar
  71. 71.
    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:e124PubMedCrossRefGoogle Scholar
  72. 72.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178PubMedCrossRefGoogle Scholar
  73. 73.
    Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem 20:947–956PubMedCrossRefGoogle Scholar
  74. 74.
    Jou I, Lee JH, Park SY, Yoon HJ, Joe EH, Park EJ (2006) Gangliosides trigger inflammatory responses via TLR4 in brain glia. Am J Pathol 168:1619–1630PubMedCrossRefGoogle Scholar
  75. 75.
    Glezer I, Lapointe A, Rivest S (2006) Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J 20:750–752PubMedGoogle Scholar
  76. 76.
    Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR (2005) Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J Immunol 175:4189–4193PubMedGoogle Scholar
  77. 77.
    Visser L, Jan de Heer H, Boven LA, van Riel D, van Meurs M, Melief MJ, Zahringer U, van Strijp J, Lambrecht BN, Nieuwenhuis EE, Laman JD (2005) Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease. J Immunol 174:808–816PubMedGoogle Scholar
  78. 78.
    Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA (2006) Microglia recognize double-stranded RNA via TLR3. J Immunol 176:3804–3812PubMedGoogle Scholar
  79. 79.
    Kawai T, Akira S (2007) Antiviral signaling through pattern recognition receptors. J Biochem 141:137–145PubMedCrossRefGoogle Scholar
  80. 80.
    Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021PubMedGoogle Scholar
  81. 81.
    Iliev AI, Stringaris AK, Nau R, Neumann H (2004) Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). FASEB J 18:412–414PubMedGoogle Scholar
  82. 82.
    Prinz M, Garbe F, Schmidt H, Mildner A, Gutcher I, Wolter K, Piesche M, Schroers R, Weiss E, Kirschning CJ, Rochford CD, Bruck W, Becher B (2006) Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J Clin Invest 116:456–464PubMedCrossRefGoogle Scholar
  83. 83.
    Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, Carrio R, Merino J, Liu D, Ni J, Nunez G (1999) Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 274:14560–14567PubMedCrossRefGoogle Scholar
  84. 84.
    Kanneganti TD, Lamkanfi M, Nunez G (2007) Intracellular NOD-like receptors in host defense and disease. Immunity 27:549–559PubMedCrossRefGoogle Scholar
  85. 85.
    Melchjorsen J, Jensen SB, Malmgaard L, Rasmussen SB, Weber F, Bowie AG, Matikainen S, Paludan SR (2005) Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner. J Virol 79:12944–12951PubMedCrossRefGoogle Scholar
  86. 86.
    Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD (2009) Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab 29:534–544PubMedCrossRefGoogle Scholar
  87. 87.
    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-beta. Nat Immunol 9:857–865PubMedCrossRefGoogle Scholar
  88. 88.
    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
  89. 89.
    Monif M, Reid CA, Powell KL, Smart ML, Williams DA (2009) The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. J Neurosci 29:3781–3791PubMedCrossRefGoogle Scholar
  90. 90.
    Sanz JM, Chiozzi P, Ferrari D, Colaianna M, Idzko M, Falzoni S, Fellin R, Trabace L, Di Virgilio F (2009) Activation of microglia by amyloid beta requires P2X7 receptor expression. J Immunol 182:4378–4385PubMedCrossRefGoogle Scholar
  91. 91.
    Takenouchi T, Nakai M, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Wei J, Sekigawa A, Sato M, Kojima S, Kitani H, Hashimoto M (2009) The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J Immunol 182:2051–2062PubMedCrossRefGoogle Scholar
  92. 92.
    Sharp AJ, Polak PE, Simonini V, Lin SX, Richardson JC, Bongarzone ER, Feinstein DL (2008) P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J Neuroinflammation 5:33PubMedCrossRefGoogle Scholar
  93. 93.
    Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29:3518–3528PubMedCrossRefGoogle Scholar
  94. 94.
    Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (2008) Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268PubMedCrossRefGoogle Scholar
  95. 95.
    Fujita R, Ma Y, Ueda H (2008) Lysophosphatidic acid-induced membrane ruffling and brain-derived neurotrophic factor gene expression are mediated by ATP release in primary microglia. J Neurochem 107:152–160PubMedCrossRefGoogle Scholar
  96. 96.
    Rothwell NJ, Luheshi GN (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 23:618–625PubMedCrossRefGoogle Scholar
  97. 97.
    Davies CA, Loddick SA, Toulmond S, Stroemer RP, Hunt J, Rothwell NJ (1999) The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 19:87–98PubMedCrossRefGoogle Scholar
  98. 98.
    Streit WJ, Hurley SD, McGraw TS, Semple-Rowland SL (2000) Comparative evaluation of cytokine profiles and reactive gliosis supports a critical role for interleukin-6 in neuron–glia signaling during regeneration. J Neurosci Res 61:10–20PubMedCrossRefGoogle Scholar
  99. 99.
    Mizuno T, Sawada M, Marunouchi T, Suzumura A (1994) Production of interleukin-10 by mouse glial cells in culture. Biochem Biophys Res Commun 205:1907–1915PubMedCrossRefGoogle Scholar
  100. 100.
    Strle K, Zhou JH, Broussard SR, Venters HD, Johnson RW, Freund GG, Dantzer R, Kelley KW (2002) IL-10 promotes survival of microglia without activating Akt. J Neuroimmunol 122:9–19PubMedCrossRefGoogle Scholar
  101. 101.
    Boche D, Cunningham C, Docagne F, Scott H, Perry VH (2006) TGFbeta1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol Dis 22:638–650PubMedCrossRefGoogle Scholar
  102. 102.
    Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS (2001) Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. J Neurochem 77:182–189PubMedCrossRefGoogle Scholar
  103. 103.
    Schlapbach R, Spanaus KS, Malipiero U, Lens S, Tasinato A, Tschopp J, Fontana A (2000) TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Eur J Immunol 30:3680–3688PubMedCrossRefGoogle Scholar
  104. 104.
    Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7:612–618PubMedCrossRefGoogle Scholar
  105. 105.
    Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 2:788–794PubMedCrossRefGoogle Scholar
  106. 106.
    Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, O'Callaghan JP (2006) Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha. FASEB J 20:670–682PubMedCrossRefGoogle Scholar
  107. 107.
    Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U (2002) Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci 22:RC216PubMedGoogle Scholar
  108. 108.
    Dolga AM, Granic I, Blank T, Knaus HG, Spiess J, Luiten PG, Eisel UL, Nijholt IM (2008) TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappaB-dependent up-regulation of K2.2 channels. J Neurochem 107:1158–1167PubMedGoogle Scholar
  109. 109.
    Stagi M, Gorlovoy P, Larionov S, Takahashi K, Neumann H (2006) Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway. FASEB J 20:2573–2575PubMedCrossRefGoogle Scholar
  110. 110.
    Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A (2009) A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat Neurosci 12:387–389PubMedCrossRefGoogle Scholar
  111. 111.
    Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D'Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Cencioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 29:3442–3452PubMedCrossRefGoogle Scholar
  112. 112.
    Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59PubMedCrossRefGoogle Scholar
  113. 113.
    Retamal MA, Froger N, Palacios-Prado N, Ezan P, Saez PJ, Saez JC, Giaume C (2007) Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J Neurosci 27:13781–13792PubMedCrossRefGoogle Scholar
  114. 114.
    Romero-Sandoval EA, Horvath RJ, DeLeo JA (2008) Neuroimmune interactions and pain: focus on glial-modulating targets. Curr Opin Investig Drugs 9:726–734PubMedGoogle Scholar
  115. 115.
    Jang S, Kelley KW, Johnson RW (2008) Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A 105:7534–7539PubMedCrossRefGoogle Scholar
  116. 116.
    Hendriks JJ, Alblas J, van der Pol SM, van Tol EA, Dijkstra CD, de Vries HE (2004) Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med 200:1667–1672PubMedCrossRefGoogle Scholar
  117. 117.
    Mika J (2008) Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep 60:297–307PubMedGoogle Scholar
  118. 118.
    El-Benna J, Dang PM, Gougerot-Pocidalo MA, Elbim C (2005) Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses. Arch Immunol Ther Exp (Warsz) 53:199–206Google Scholar
  119. 119.
    Babior BM (2000) Phagocytes and oxidative stress. Am J Med 109:33–44PubMedCrossRefGoogle Scholar
  120. 120.
    Kishida KT, Pao M, Holland SM, Klann E (2005) NADPH oxidase is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1. J Neurochem 94:299–306PubMedCrossRefGoogle Scholar
  121. 121.
    Kishida KT, Klann E (2007) Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal 9:233–244PubMedCrossRefGoogle Scholar
  122. 122.
    Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA (2005) Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci U S A 102:9936–9941PubMedCrossRefGoogle Scholar
  123. 123.
    Cheret C, Gervais A, Lelli A, Colin C, Amar L, Ravassard P, Mallet J, Cumano A, Krause KH, Mallat M (2008) Neurotoxic activation of microglia is promoted by a nox1-dependent NADPH oxidase. J Neurosci 28:12039–12051PubMedCrossRefGoogle Scholar
  124. 124.
    Liu Y, Hao W, Letiembre M, Walter S, Kulanga M, Neumann H, Fassbender K (2006) Suppression of microglial inflammatory activity by myelin phagocytosis: role of p47-PHOX-mediated generation of reactive oxygen species. J Neurosci 26:12904–12913PubMedCrossRefGoogle Scholar
  125. 125.
    Olofsson P, Holmberg J, Tordsson J, Lu S, Akerstrom B, Holmdahl R (2003) Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet 33:25–32PubMedCrossRefGoogle Scholar
  126. 126.
    Merrill JE (1992) Proinflammatory and antiinflammatory cytokines in multiple sclerosis and central nervous system acquired immunodeficiency syndrome. J Immunother (1991) 12:167–170CrossRefGoogle Scholar
  127. 127.
    Hofman FM, Hinton DR, Johnson K, Merrill JE (1989) Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170:607–612PubMedCrossRefGoogle Scholar
  128. 128.
    Vodovotz Y, Bogdan C (1994) Control of nitric oxide synthase expression by transforming growth factor-beta: implications for homeostasis. Prog Growth Factor Res 5:341–351PubMedCrossRefGoogle Scholar
  129. 129.
    Drapier JC, Hibbs JB Jr (1988) Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron–sulfur enzymes in the macrophage effector cells. J Immunol 140:2829–2838PubMedGoogle Scholar
  130. 130.
    Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250PubMedGoogle Scholar
  131. 131.
    Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS et al (1991) DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 254:1001–1003PubMedCrossRefGoogle Scholar
  132. 132.
    Stagi M, Dittrich PS, Frank N, Iliev AI, Schwille P, Neumann H (2005) Breakdown of axonal synaptic vesicle precursor transport by microglial nitric oxide. J Neurosci 25:352–362PubMedCrossRefGoogle Scholar
  133. 133.
    Gorlovoy P, Larionov S, Pham TT, Neumann H (2009) Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J 23:2502–2513PubMedCrossRefGoogle Scholar
  134. 134.
    Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH Jr (2004) Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43:19–30PubMedCrossRefGoogle Scholar
  135. 135.
    Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of CologneCologneGermany
  2. 2.Institute of Reconstructive Neurobiology, University Hospital BonnUniversity Bonn and Hertie-FoundationBonnGermany

Personalised recommendations