Microglia phenotype diversity

CNS and Neurological Disorders - Drug Targets

Volumn 10, Issue 1, 2011, Pages 108-118

  Olah, M ^a   Biber, K ^a,b   Vinet, J ^a   Boddeke, H W G M ^a  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^b UNIVERSITY OF FREIBURG   (Germany)

Author keywords

Aging; Gliomas; Grey matter; Inflammation; Microglia; White matter

Indexed keywords

AGING; BRAIN REGION; BRAIN TUMOR; CENTRAL NERVOUS SYSTEM; DENDRITIC CELL; GLIOMA; GRAY MATTER; HUMAN; MICROGLIA; NERVOUS SYSTEM DEVELOPMENT; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PHENOTYPE; REVIEW; WHITE MATTER; BRAIN; CELL CULTURE; INFLAMMATION; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY;

AGING; BRAIN; BRAIN NEOPLASMS; CELLS, CULTURED; HUMANS; INFLAMMATION; MICROGLIA; NEUROGENESIS; PHENOTYPE;

EID: 79960990312     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/187152711794488575     Document Type: Review

References (179)

1. del Rio-Hortega, P. Microglia. In: Penfield W., Ed. Cytology and Cellular Pathology of the Nervous System. New York: Paul B. Hoeber. 1932, pp. 482-534.
2. Ransohoff, R.M.; Perry V.H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol., 2009, 27, 119-145.
3. Kraft, A.D.; McPherson, C.A.; Harry, G.J. Heterogeneity of microglia and TNF signaling as determinants for neuronal death or survival. Neurotoxicology, 2009, 30, 785-793.
4. Carson, M.J.; Bilousova, T.V.; Puntambekar, S.S.; Melchior, B.; Doose, J.M.; Ethell, I.M. A rose by any other name? The potential consequences of microglial heterogeneity during CNS health and disease. Neurotherapeutics, 2007, 4, 571-579.
5. Hanisch, U.K.; Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci., 2007, 11, 1387-1394.
6. Lawson, L.J.; Perry, V.H.; Dri, P.; Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience, 1990, 39, 151-170.
7. Mittelbronn, M.; Dietz, K.; Schluesener, H.J.; Meyermann, R. Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol., 2001, 101, 249-255.
8. Savchenko, V.L.; McKanna, J.A.; Nikonenko, I.R.; Skibo, G.G. Microglia and astrocytes in the adult rat brain: comparative immunocytochemical analysis demonstrates the efficacy of lipocortin 1 immunoreactivity. Neuroscience, 2000, 96, 195-203.
9. Ji, K.A.; Eu, M.Y.; Kang, S.H.; Gwag, B.J.; Jou, I.; Joe, E.H. Differential neutrophil infiltration contributes to regional differences in brain inflammation in the substantia nigra pars compacta and cortex. Glia, 2008, 56, 1039-1047.
10. Kim, W.G.; Mohney, R.P.; Wilson, B.; Jeohn, G.H.; Liu, B.; Hong, J.S. Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J. Neurosci., 2000, 20, 6309-6316.
11. Hurley, S.D.; O'Banion, M.K.; Song, D.D.; Arana, F.S.; Olschowka, J.A.; Haber, S.N. Microglial response is poorly correlated with neurodegeneration following chronic, low-dose MPTP administration in monkeys. Exp. Neurol., 2003, 184, 659-668.
12. Soltys, Z.; Orzylowska-Sliwinska, O.; Zaremba, M.; Orlowski, D.; Piechota, M.; Fiedorowicz, A.; Janeczko, K.; Oderfeld-Nowak, B. Quantitative morphological study of microglial cells in the ischemic rat brain using principal component analysis. J. Neurosci. Methods, 2005, 146, 50-60.
13. Xie, Z; Morgan, T.E.; Rozovsky, I.; Finch, C.E. Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp. Neurol., 2003, 182, 135-141.
14. Ren, L.; Lubrich, B.; Biber, K.; Gebicke-Haerter P.J. Differential expression of inflammatory mediators in rat microglia cultured from different brain regions. Brain Res. Mol. Brain Res., 1999, 65, 198-205.
15. Guo, L.; Sawkar, A.; Zasadzki, M.; Watterson, D.M.; Van Eldik, L.J. Similar Activation of glial cultures from different rat brain regions by neuroinflammatory stimuli and downregulation of the activation by a new class of small molecule ligands. Neurobiol. Aging, 2001, 22, 975-981.
16. De Haas, A.H.; Boddeke, H.W.G.M.; Biber, K. Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia, 2008, 56, 888-894.
17. Wu, C.H.; Chien, H.F.; Chang, C.Y.; Ling, E.A. Heterogeneity of antigen expression and lectin labeling on microglial cells in the olfactory bulb of adult rats. Neurosci. Res., 1997, 28, 67-75.
18. Jiang-Shieh, Y.F.; Wu, C.H.; Chang, M.L.; Shieh, J.Y.; Wen, C.Y. Regional heterogeneity in immunoreactive macrophages/microglia in the rat pineal gland. J. Pineal. Res., 2003, 35, 45-53.
19. Ayoub, A.E.; Salm, A.K. Increased morphological diversity of microglia in the activated hypothalamic supraoptic nucleus. J. Neurosci., 2003, 23, 7759-7766.
20. Ehninger, D.; Kempermann, G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb. Cortex, 2003, 13, 845-851.
21. Streit, W.J.; Graeber, M.B. Heterogeneity of microglial and perivascular cell populations: insights gained from the facial nucleus paradigm. Glia, 1993, 7, 68-74.
22. Ladeby, R.; Wirenfeldt, M.; Dalmau, I.; Gregersen, R.; Garcia-Ovejero D, Babcock A, Owens T, Finsen B. Proliferating resident microglia express the stem cell antigen CD34 in response to acute neural injury. Glia, 2005, 50, 121-131.
23. Ribes, S.; Ebert, S.; Regen, T.; Czesnik, D.; Scheffel, J.; Zeug, A.; Bunkowski, S.; Eiffert, H.; Hanisch, U.K.; Hammerschmidt, S.; Nau, R. 2010. Fibronectin stimulates Escherichia coli phagocytosis by microglial cells. Glia, 2010, 58, 367-376.
24. Milner, R; Campbell, I.L. The extracellular matrix and cytokines regulate microglial integrin expression and activation. J. Immunol., 2003, 170, 3850-3858.
25. Zhao, T.Z.; Xia, Y.Z.; Li, L.; Li, J.; Zhu, G.; Chen, S.; Feng, H.; Lin, J.K. Bovine serum albumin promotes IL-1beta and TNF-alpha secretion by N9 microglial cells. Neurol. Sci., 2009, 30, 379-383.
26. Si, Q.; Nakamura, Y.; Kataoka, K. A serum factor enhances production of nitric oxide and tumor necrosis factor-alpha from cultured microglia. Exp. Neurol., 2000, 162, 89-97.
27. Mander, T.H.; Morris, J.F. Immunophenotypic evidence for distinct populations of microglia in the rat hypothalamo-neurohypophysial system. Cell Tissue Res., 1995, 280, 665-673.
28. Biber, K.; Neumann, H.; Inoue, K.; Boddeke H.W.G.M. Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci., 2007, 30, 596-602.
29. Deckert, M.; Sedgwick, J.D.; Fischer, E.; Schluter, D. Regulation of microglial cell responses in murine Toxoplasma encephalitis by CD200/CD200 receptor interaction. Acta Neuropathol., 2006, 111, 548-558.
30. Cardona, A.E.; Pioro, E.P.; Sasse, M.E.; Kostenko, V.; Cardona, S.M.; Dijkstra I.M.; Huang, D.; Kidd, G.; Dombrowski, S.; Dutta, R.; Lee, J.C.; Cook, D.N.; Jung, S.; Lira, S.A.; Littman, D.R.; Ransohoff, R.M. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci., 2006, 9, 917-924.
31. Pocock, J.M.; Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci., 2007, 30, 527-535.
32. Farber, K.; Pannasch, U.; Kettenmann, H. Dopamine and noradrenaline control distinct functions in rodent microglial cells. Mol. Cell. Neurosci., 2005, 29, 128-138.
33. Du, Y.; Fischer, T.Z.; Lee L.N.; Lercher, L.D.; Dreyfus, C.F. Regionally specific effects of BDNF on oligodendrocytes. Dev. Neurosci., 2003, 25, 116-126.
34. Olsen, M.L.; Campbell S.L.; Sontheimer, H. Differential distribution of Kir4.1 in spinal cord astrocytes suggests regional differences in K+ homeostasis. J. Neurophysiol., 2007, 98, 786-793.
35. Kreutzberg G.W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci., 1996, 8, 312-318.
36. Van Rossum D.; Hanisch U.K. Microglia. Metab. Brain Dis., 2004, 19, 393-411.
37. Streit, W.J. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia, 2002. 40, 133-139.
38. Sanchez-Guajardo, V.; Febbraro, F.; Kirik, D.; Romero-Ramos, M. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson's disease. PLoS One, 2010, 5, e8784.
39. Turrin, N.P.; Rivest, S.; Molecular and cellular immune mediators of neuroprotection. Mol. Neurobiol., 2006, 34, 221-242.
40. Lalancette-Hébert, M.; Gowing, G.; Simard, A.; Weng, Y.C.; Kriz, J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci., 2007, 27, 2596-2605.
41. Boillée, S.; Vande Velde, C; Cleveland D.W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron, 2006, 52, 39-59.
42. El Khoury, J.; Hickman, S.E.; Thomas, C.A.; Loike, J.D.; Silverstein, S.C. Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease. Neurobiol. Aging, 1998, 19, 81-84.
43. Neumann, H.; Takahashi, K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 [TREM2] for central nervous tissue immune homeostasis. J. Neuroimmunol., 2007, 184, 92-99.
44. Streit, W.J. Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci., 2006, 9, 506-510.
45. Bernstein, HG; Steiner, J; Bogerts, B. Glial cells in schizophrenia: pathophysiological significance and possible consequences for therapy. Expert Rev. Neurother., 2009, 7, 1059-1071.
46. Müller, N.; Schwarz, M.J. Immunological aspects of depressive disorders. Nervenarzt, 2007, 78, 1261-1273.
47. Gordon, S. Elie Metchnikoff: father of natural immunity. Eur. J. Immunol., 2008, 38, 3257-3264.
48. Martinez, F.O.; Helming, L.; Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol., 2009, 27, 451-483.
49. Mantovani, A. From phagocyte diversity and activation to probiotics: back to Metchnikoff. Eur. J. Immunol., 2008, 38, 3269-3273.
50. Mosser, D.M.; Edwards J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol., 2008, 12, 958-969.
51. Colton, C.A. Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune Pharmacol., 2009, 4, 399-418.
52. Butovsky, O.; Bukshpan, S.; Kunis, G.; Jung, S.; Schwartz, M. Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers. Mol. Cell. Neurosci., 2007, 35, 490-500.
53. Gottfried-Blackmore, A.; Kaunzner, U.W.; Idoyaga, J.; Felger, J.C.; McEwen, B.S.; Bulloch, K. Acute in vivo exposure to interferon{gamma} enables resident brain dendritic cells to become effective antigen presenting cells. Proc. Natl. Acad. Sci. USA, 2009, 106(49). 20918-20923.
54. Ponomarev, E.D.; Maresz, K.; Tan, Y.; Dittel, B.N. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J. Neurosci., 2007, 40, 10714-10721.
55. Sedgwick, J.D.; Ford, A.L.; Foulcher, E.; Airriess, R. Central nervous system microglial cell activation and proliferation follows direct interaction with tissue-infiltrating T cell blasts. J. Immunol., 1998, 160, 5320-5330.
56. Remington, L.T.; Babcock, A.A.; Zehntner, S.P.; Owens, T. Microglial recruitment, activation, and proliferation in response to primary demyelination. Am. J. Pathol., 2007, 170, 1713-1724.
57. De Haas, A.H.; Boddeke, H.W.G.M.; Brouwer N.; Biber K. Optimized isolation enables ex vivo analysis of microglia from various central nervous system regions. Glia, 2007, 55, 1374-1384.
58. Stenzel, W.; Müller, U.; Köhler, G.; Heppner, F.L., Blessing, M.; McKenzie, A.N. Brombacher, F.; Alber, G. IL-4/IL-13-dependent alternative activation of macrophages but not microglial cells is associated with uncontrolled cerebral cryptococcosis. Am. J. Pathol., 2009, 174, 486-496.
59. Steinman, R.M.; Banchereau, J. Taking dendritic cells into medicine. Nature, 2007, 449, 419-426.
60. Matyszak, M.K.; Perry, V.H. The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience, 1996, 74, 599-608.
61. Fischer, H.G.; Bonifas, U.; Reichmann, G.; Phenotype and functions of brain dendritic cells emerging during chronic infection of mice with Toxoplasma gondii. J. Immunol., 2000, 164, 4826-4834.
62. Fischer, H.G.; Reichmann, G. Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J. Immunol., 2001, 166, 2717-2726.
63. Reichmann, G.; Schroeter, M.; Jander, S.; Fischer, H.G. Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J. Neuroimmunol., 2002, 129, 125-132.
64. Bulloch, K.; Miller, M.M.; Gal-Toth, J.; Milner T.A.; GottfriedBlackmore A.; Waters E.M.; Kaunzner U.W.; Liu K.; Lindquist R.; Nussenzweig, M.C.; Steinman R.M.; McEwen B.S. CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J. Comp. Neurol., 2008, 508, 687-710.
65. Felger, J.C.; Abe T.; Kaunzner U.W.; Gottfried-Blackmore, A.; Gal-Toth, J.; McEwen, B.S.; Iadecola, C.; Bulloch, K. Brain dendritic cells in ischemic stroke: Time course, activation state, and origin. Brain Behav. Immun., 2010, 24(5), 724-737.
66. Mausberg, A.K.; Jander, S.; Reichmann, G.; Intracerebral granulocytemacrophage colony-stimulating factor induces functionally competent dendritic cells in the mouse brain. Glia, 2009, 57, 1341-1350.
67. Santambrogio, L.; Belyanskaya, S.L.; Fischer, F.R.; Cipriani, B.; Brosnan, C.F.; Ricciardi-Castagnoli, P.; Stern, L.J.; Strominger, J.L.; Riese, R. Developmental plasticity of CNS microglia. Proc. Natl. Acad. Sci. USA, 2001, 98, 6295-6300.
68. Suh, H.; Deng, W.; Gage, F.H. Signaling in adult neurogenesis. Annu. Rev. Cell Dev. Biol., 2009, 25, 253-275.
69. Gould, E. How widespread is adult neurogenesis in mammals? Nat. Rev. Neurosci., 2007, 8, 481-488.
70. Kempermann, G.; Jessberger, S.; Steiner, B.; Kronenberg, G. Milestones of neuronal development in the adult hippocampus. Trends Neurosci., 2004, 27, 447-452.
71. Gross, C.G. Neurogenesis in the adult brain: death of a dogma. Nat. Rev. Neurosci., 2000, 1, 67-73.
72. Chang, A.; Smith, M.C.; Yin, X.; Fox, R.J.; Staugaitis, S.M.; Trapp, B.D. Neurogenesis in the chronic lesions of multiple sclerosis. Brain, 2008, 131, 2366-2375.
73. Aarum, J.; Sandberg, K.; Haeberlein, S.L.; Persson, M.A. Migration and differentiation of neural precursor cells can be directed by microglia. Proc. Natl. Acad. Sci. USA, 2003, 100, 15983-15988.
74. Das, S.; Basu, A. Inflammation: a new candidate in modulating adult neurogenesis. J. Neurosci. Res., 2008, 86, 1199-1208.
75. Simard, A.R.; Rivest, S. Role of inflammation in the neurobiology of stem cells. Neuroreport, 2004, 15, 2305-2310.
76. Battista, D.; Ferrari, C.C.; Gage, F.H.; Pitossi, F.J. Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus. Eur. J. Neurosci., 2006, 23, 83-93.
77. Wachs, F.P.; Winner, B.; Couillard-Despres, S.; Schiller, T.; Aigner, R.; Winkler, J; Bogdahn, U.; Aigner, L. Transforming growth factor-beta1 is a negative modulator of adult neurogenesis. J. Neuropathol. Exp. Neurol., 2006, 65, 358-370.
78. Ziv, Y.; Ron, N.; Butovsky, O.; Landa, G.; Sudai, E.; Greenberg, N.; Cohen, H.; Kipnis, J.; Schwartz, M. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci., 2006, 9, 268-275.
79. Olah, M.; Ping, G.; De Haas, A.H.; Brouwer, N.; Meerlo, P.; Van der Zee, E.A.; Biber, K.; Boddeke, H.W.G.M. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia, 2009, 57, 1046-1061.
80. Walton, N.M.; Sutter, B.M.; Laywell, E.D.; Levkoff, L.H.; Kearns, S.M.; Marshall, G.P. Scheffler, B.; Steindler, D.A. Microglia instruct subventricular zone neurogenesis. Glia, 2006, 54, 815-825.
81. Cacci, E., Jmone-Cat, M.A.; Anelli, T.; Biagioni, S.; Minghetti, L. In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia. Glia, 2008, 56, 412-425.
82. Ekdahl, C.T.; Kokaia, Z.; Lindvall, O. Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience, 2009, 158, 1021-1029.
83. Whitney, N.P.; Eidem, T.M.; Peng, H.; Huang, Y.; Zheng, J.C. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J. Neurochem., 2009, 108, 1343-1359.
84. Balasubramaniam, B.; Carter, D.A.; Mayer, E.J.; Dick, A.D. Microglia derived IL-6 suppresses neurosphere generation from adult human retinal cell suspensions. Exp. Eye Res., 2009, 89, 757-766.
85. Butovsky, O.; Landa, G.; Kunis, G.; Ziv, Y.; Avidan, H.; Greenberg, N.; Schwartz, A.; Smirnov, I.; Pollack, A.; Jung, S.; Schwartz, M. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J. Clin. Invest., 2006a, 116, 905-915.
86. Butovsky, O.; Ziv, Y.; Schwartz, A.; Landa, G.; Talpalar A.E.; Pluchino, S.; Martino, G.; Schwartz, M. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci., 2006, 31, 149-160.
87. Liu YP, Lin HI, Tzeng SF. Tumor necrosis factor-alpha and interleukin18 modulate neuronal cell fate in embryonic neural progenitor culture. Brain Res., 2005, 1054, 152-158.
88. Cacci, E.; Claasen, J.H.; Kokaia, Z. Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J. Neurosci. Res., 2005, 80, 789-797.
89. Liao, H.; Huang, W.; Niu, R.; Sun, L.; Zhang, L. Cross-talk between the epidermal growth factor-like repeats/fibronectin 6-8 repeats domains of Tenascin-R and microglia modulates neural stem/progenitor cell proliferation and differentiation. J. Neurosci. Res., 2008, 86, 27-34.
90. Zhu, P.; Hata, R.; Cao, F.; Gu, F.; Hanakawa, Y.; Hashimoto, K.; Sakanaka, M. Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function. FASEB J., 2008, 22, 3866-3877.
91. Nakanishi, M.; Niidome, T.; Matsuda, S.; Akaike, A.; Kihara, T.; Sugimoto, H. Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur. J. Neurosci., 2007, 25, 649-658.
92. Kim, B.J.; Kim, M.J.; Park, J.M.; Lee, S.H.; Kim, Y.J.; Ryu, S.; Kim, Y.H.; Yoon, B.W. Reduced neurogenesis after suppressed inflammation by minocycline in transient cerebral ischemia in rat. J. Neurol. Sci., 2009, 279, 70-75.
93. Choi, S.H.; Veeraraghavalu, K.; Lazarov, O.; Marler, S.; Ransohoff, R.M.; Ramirez, J.M.; Sisodia, S.S. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron, 2008, 59, 568-580.
94. Jakubs, K.; Bonde, S.; Iosif, R.E.; Ekdahl, C.T.; Kokaia, Z.; Kokaia, M.; Lindvall, O. Inflammation regulates functional integration of neurons born in adult brain. J. Neurosci., 2008, 28, 12477-12488.
95. Spulber, S.; Oprica, M.; Bartfai, T.; Winblad, B.; Schultzberg, M. Blunted neurogenesis and gliosis due to transgenic overexpression of human soluble IL-1ra in the mouse. Eur. J. Neurosci., 2008, 27, 549-558.
96. Bonde, S.; Ekdahl, C.T.; Lindvall, O. Long-term neuronal replacement in adult rat hippocampus after status epilepticus despite chronic inflammation. Eur. J. Neurosci., 2006, 23, 965-974.
97. Ekdahl, C.T.; Claasen, J.H.; Bonde, S.; Kokaia, Z.; Lindvall, O. Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl. Acad. Sci. USA, 2003, 100, 13632-13637.
98. Monje, M.L.; Toda, H.; Palmer, T.D. Inflammatory blockade restores adult hippocampal neurogenesis. Science, 2003, 302, 1760-1765.
99. Marshall, G.P.; Demir, M.; Steindler, D.A.; Laywell, E.D. Subventricular zone microglia possess a unique capacity for massive in vitro expansion. Glia, 2008, 56, 1799-1808.
100. Thored, P.; Heldmann, U.; Gomes-Leal, W.; Gisler, R.; Darsalia, V.; Taneera, J.; Nygren J.M.; Jacobsen, S.E.; Ekdahl, C.T.; Kokaia, Z.; Lindvall, O. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia, 2009, 57, 835-849.
101. Rahpeymai, Y.; Hiet-aletal/et-ala, M.A.; Wilhelmsson, U.; Fotheringham, A.; Davies, I.; Nilsson, A.K.; Zwirner, J.; Wetsel, R.A.; Gerard, C.; Pekny, M.; Pekna, M. Complement: a novel factor in basal and ischemiainduced neurogenesis. EMBO J., 2006, 25, 1364-1374.
102. Vincent, A.J.; Lau, P.W.; Roskams, A.J. SPARC is expressed by macroglia and microglia in the developing and mature nervous system. Dev. Dyn., 2008, 237, 1449-1462.
103. Goncalves, M.B.; Williams, E.J.; Yip, P.; Yanez-Munoz R.J.; Williams, G.; Doherty, P. The COX-2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brain. Br. J. Pharmacol. 2010 [Epub ahead of print].
104. Styren, S.D.; Civin, W.H.; Rogers, J. Molecular, cellular, and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer's disease brain. Exp. Neurol., 1990, 110, 93-104.
105. Sasaki, A.; Nakazato, Y. The identity of cells expressing MHC class II antigens in normal and pathological human brain. Neuropathol. Appl. Neurobiol., 1992, 18, 13-26.
106. Gehrmann, J.; Banati, R.B.; Kreutzberg, G.W. Microglia in the immune surveillance of the brain: human microglia constitutively express HLADR molecules. J. Neuroimmunol., 1993, 48, 189-198.
107. Ogura, K.; Ogawa, M.; Yoshida, M. Effects of ageing on microglia in the normal rat brain: immunohistochemical observations. Neuroreport, 1994, 5, 1224-1226.
108. Ong, W.Y.; Leong, S.K.; Garey, L.J.; Tan, K.K.; Zhang, H.F. A light and electron microscopic study of HLA-DR positive cells in the human cerebral cortex and subcortical white matter. J. Hirnforsch., 1995, 36, 553-563.
109. Alldinger, S.; Wunschmann, A.; Baumgartner, W; Voss, C.; Kremmer, E. Up-regulation of major histocompatibility complex class II antigen expression in the central nervous system of dogs with spontaneous canine distemper virus encephalitis. Acta Neuropathol., 1996, 92, 273-280.
110. Sheffield, L.G.; Berman, N.E. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol. Aging, 1988, 19, 47-55.
111. Anderson, A.C.; Anderson, D.E.; Bregoli, L.; Hastings, W.D.; Kassam, N.; Lei, C.; Chandwaskar, R.; Karman, J.; Su, E.W.; Hirashima, M.; Bruce, J.N.; Kane, L.P.; Kuchroo, V.K.; Hafler, D.A. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science, 2007, 318, 1141-1143.
112. Kullberg, S.; Aldskogius, H.; Ulfhake, B. Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord. Brain Res., 2001, 899, 169-186.
113. Wakita, H.; Tomimoto, H.; Akiguchi, I.; Kimura, J. Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol., 1994, 87, 484-492.
114. Wakita, H.; Tomimoto, H.; Akiguchi, I.; Kimura, J. Protective effect of cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke, 1995, 26, 1415-1422.
115. Wakita, H.; Tomimoto, H.; Akiguchi, I.; Kimura, J. Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia. Brain. Res., 1998, 792, 105-113.
116. Brink, B.P.; Veerhuis, R.; Breij, E.C.; van der Valk, P.; Dijkstra, C.D.; Bo, L. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J. Neuropathol. Exp. Neurol., 2005, 64, 147-155.
117. Bo, L. The histopathology of grey matter demyelination in multiple sclerosis. Acta Neurol. Scand., 2009, 120, 51-57.
118. Nishie, A.; Ono, M.; Shono, T.; Fukushi, J.; Otsubo, M.; Onoue, H.; Ito, Y.; Inamura, T.; Ikezaki, K.; Fukui, M.; Iwaki, T.; Kuwano, M. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin. Cancer Res., 1999, 5, 1107-1113.
119. Nishie, A.; Masuda, K.; Otsubo, M.; Migita, T.; Tsuneyoshi, M.; Kohno, K.; Shuin, T.; Naito, S.; Ono, M.; Kuwano, M. High expression of the Cap43 gene in infiltrating macrophages of human renal cell carcinomas. Clin. Cancer Res., 2001, 7, 2145-2151.
120. Watters, J.J.; Schartner, J.M.; Badie, B. Microglia function in brain tumors. J. Neurosci. Res., 2005, 81, 447-455.
121. Hussain, S.F.; Yang, D.; Suki, D.; Aldape, K.; Grimm, E.; Heimberger, A.B. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol., 2006, 8, 261-279.
122. Giometto, B.; Bozza, F.; Faresin, F.; Alessio, L.; Mingrino, S.; Tavolato, B. Immune infiltrates and cytokines in gliomas. Acta Neurochir., 1996, 138, 50-56.
123. Graeber, M.B.; Scheithauer, B.W.; Kreutzberg, G.W. Microglia in brain tumors. Glia, 2002, 40, 252-259.
124. Markovic, D.S.; Vinnakota, K.; Chirasani, S.; Synowitz, M.; Raguet, H.; Stock, K.; Sliwa, M.; Lehmann, S.; Kalin, R.; VanRooijen, N.; Holmbeck, K.; Heppner, F.L.; Kiwit, J.; Matyash, V.; Lehnardt, S.; Kaminska B, Glass R, Kettenmann H. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc. Natl. Acad. Sci. USA, 2009, 106, 12530-12535.
125. Graeber, M.B., Bise, K.; Mehraein, P. CR3/43, a marker for activated human microglia: application to diagnostic neuropathology. Neuropathol. Appl. Neurobiol., 1994, 20, 406-408.
126. Tran, C.T.; Wolz, P.; Egensperger, R.; Kosel, S.; Imai, Y.; Bise, K.; Kohsaka, S.; Mehraein, P.; Graeber, M.B. Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance. Neuropathol. Appl. Neurobiol., 1981, 24, 293-300.
127. Badie, B.; Bartley, B; Schartner, J. Differential expression of MHC class II and B7 costimulatory molecules by microglia in rodent gliomas. J. Neuroimmunol., 2002, 133, 39-45.
128. Murphy, G.M.; Bitting, L.; Majewska, A.; Schmidt, K; Song, Y.; Wood, C.R. Expression of interleukin-11 and its encoding mRNA by glioblastoma cells. Neurosci. Lett., 1995, 196, 153-156.
129. Halfter, H.; Kremerskothen, J.; Weber, J.; Hacker-Klom, U.; Barnekow, A.; Ringelstein, EB.; Stogbauer, F. Growth inhibition of newly established human glioma cell lines by leukemia inhibitory factor. J. Neuro Oncol., 1998a, 39, 1-18.
130. Halfter, H.; Lotfi, R.; Westermann, R.; Young, P.; Ringelstein, E.B.; Stogbauer, F.T. Inhibition of growth and induction of differentiation of glioma cell lines by oncostatin M [OSM]. Growth Factors, 1998b, 15, 135-147.
131. Hao, C.; Parney, I.F.; Roa, W.H.; Turner, J.; Petruk, K.C.; Ramsay, D.A. Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation. Acta Neuropathol., 2002, 103, 171-178.
132. Repovic, P.; Fears, C.Y.; Gladson, C.L.; Benveniste, E.N. OncostatinM induction of vascular endothelial growth factor expression in astroglioma cells. Oncogene, 2003, 50, 8117-8124.
133. Van Meir, E.; Sawamura, Y.; Diserens, A.C.; Hamou, M.F.; de Tribolet, N. Human glioblastoma cells release interleukin 6 in vivo and in vitro. Cancer Res., 1990, 50, 6683-6688.
134. Goswami, S.; Gupta, A.; Sharma, S.K. Interleukin-6-mediated autocrine growth promotion in human glioblastoma multiforme cell line U87MG. J. Neurochem., 1998, 71, 1837-1845.
135. Krady, J.K.; Lin, H.W.; Liberto, C.M.; Basu, A.; Kremlev, S.G.; Levison, S.W. Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. J. Neurosci. Res., 2008, 86, 1538-1547.
136. Holmberg, K.H.; Patterson, P.H. Leukemia inhibitory factor is a key regulator of astrocytic, microglial and neuronal responses in a low-dose pilocarpine injury model. Brain Res., 2006, 1075, 26-35.
137. Wei, R.; Jonakait, G.M. Neurotrophins and the anti-inflammatory agents interleukin-4 [IL-4], IL-10, IL-11 and transforming growth factor-beta1[TGF-beta1] down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat microglia. J. Neuroimmunol., 1999, 95, 8-18.
138. Constam, D.B.; Philipp, J.; Malipiero, U.V.; ten Dijke P.; Schachner, M.; Fontana, A. Differential expression of transforming growth factorbeta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. J. Immunol., 1992, 148, 1404-1410.
139. Olofsson, A.; Miyazono, K.; Kanzaki, T.; Colosetti, P.; Engstrom, U.; Heldin, C. Transforming growth factor-beta 1, -beta 2, and -beta 3 secreted by a human glioblastoma cell line: identification of small and different forms of large latent complexes. J. Biol. Chem., 1992, 267, 19482-19488.
140. Schlüter, D.; Bertsch, D.; Frei, K.; Hübers, S.B.; Wiestler, O.D.; Hof, H.; Fontana, A.; Deckert-Schlüter, M. Interferon-gamma antagonizes transforming growth factor-beta2-mediated immunosuppression in murine Toxoplasma encephalitis. J. Neuroimmunol., 1998, 81, 38-48.
141. Qian, L.; Wei, S.J.; Zhang, D.; Hu, X.; Xu Z.; Wilson B.; El-Benna J.; Hong J.S.; Flood P.M. Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J. Immunol., 2008, 181, 660-668.
142. Huettner, C.; Czub, S.; Kerkau, S.; Roggendorf, W.; Tonn, J.C. Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res., 1997, 17, 3217-3224.
143. Ledeboer, A.; Brevé J.J.; Poole, S.; Tilders, F.J.; Van Dam A.M. 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, 2000, 30,134-142.
144. Marques, C.P.; Hu, S.; Sheng, W.; Cheeran, M.C.; Cox, D.; Lokensgard, J.R. Interleukin-10 attenuates production of HSV-induced inflammatory mediators by human microglia. Glia, 2004, 47, 358-366.
145. Flatten, M.; Kretz, A.; Naumann, U.; Aulwurm, S.; Egashira, K.; Isenmann, S.; Weller, M. Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann. Neurol., 2003, 54, 388-392.
146. Rao, J.S. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat. Rev. Cancer, 2003, 3, 489-501.
147. Bettinger, I.; Thanos, S.; Paulus, W. Microglia promote glioma migration. Acta Neuropathol., 2002, 103, 351-355.
148. Markovic, D.S.; Glass, R.; Synowitz, M.; VanRooijen, N.; Kettenmann, H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metallo-protease-2. J. Neuropathol. Exp. Neurol., 2005, 64, 754-762.
149. Alterman, R.L.; Stanley, E.R. Colony stimulating factor-1 expression in human glioma. Mol. Chem. Neuropathol., 1994, 21, 177-188.
150. Galasso, J.M.; Stegman, L.D.; Blaivas, M.; Harrison, J.K.; Ross, B.D.; Silverstein, F.S. Experimental gliosarcoma induces chemokine receptor expression in rat brain. Exp. Neurol., 2000, 161, 85-95.
151. Kielian, T.; Van Rooijen, N.; Hickey, W.F. MCP-1 expression in CNS1 astrocytoma cells: implications for macrophage infiltration into tumors in vivo. J. Neuro. Oncol., 2002, 56, 1-12.
152. Desbaillets, I.; Tada, M.; De Tribolet, N.; Diserens, A.C.; Hamou, M.F.; Van Meir E.G. Human astrocytomas and glioblastomas express monocyte chemoattractant protein-1 [MCP-1] in vivo and in vitro. Int. J. Cancer, 1994, 58, 240-247.
153. Takeshima, H.; Kuratsu, J.; Takeya, M.; Yoshimura, T.; Ushio, Y. Expression and localization of messenger RNA and protein for monocyte chemoattractant protein-1 in human malignant glioma. J. Neurosurg., 1994, 80, 1056-1062.
154. Brown, C.E.; Vishwanath R.P.; Aguilar, B.; Starr, R.; Najbauer, J.; Aboody, K.S; Jensen M.C. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J. Immunol., 2007, 179, 3332-3341.
155. Jordan, J.T.; Sun, W.; Hussain, S.F.; Deangulo, G.; Prabhu, S.S.; Heimberger, A.B. Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol. Immunother., 2008, 57, 123-131.
156. Leung, S.Y.; Wong, M.P.; Chung, L.P.; Chan, A.S.; Yuen, S.T. Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol., 1997, 93, 518-527.
157. Platten, M.; Kretz, A.; Naumann, U.; Aulwurm, S.; Egashira, K.; Isenmann, S.; Weller, M. Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann. Neurol., 2003, 54, 388-392.
158. Sierra, A.; Gottfried-Blackmore, A.C.; McEwen, B.S.; Bulloch, K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia, 2007, 55, 412-424.
159. Vaughan, D.W.; Peters, A. Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J. Neurocytol., 1974, 4, 405-429.
160. Perry, V.H.; Matyszak, M.K.; Fearn, S. Altered antigen expression of microglia in the aged rodent CNS. Glia, 1993, 7, 60-67.
161. Peters, A.; Josephson, K.; Vincent, S.L. Effects of aging on the neuroglial cells and pericytes within area 17 of the rhesus monkey cerebral cortex. Anat. Rec., 1991, 229, 384-398.
162. Sloane, J.A., Hollander, W.; Moss, M.B.; Rosene, D.L.; Abraham, C.R. Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol. Aging, 1999, 20, 395-405.
163. Peters, A.; Sethares, C.; The effects of age on the cells in layer 1 of primate cerebral cortex. Cereb. Cortex, 2002, 12, 27-36.
164. DiPatre, P.L.; Gelman, B.B. Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus. J. Neuropathol. Exp. Neurol., 1997, 56, 143-149.
165. Sheng, J.G.; Mrak, R.E.; Griffin, W.S. Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol., 1998, 95, 229-234.
166. Godbout, J.P.; Chen, J.; Abraham, J.; Richwine, A.F.; Berg, B.M.; Kelley, K.W.; Johnson R.W. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J., 2005, 10, 1329-1331.
167. Ye, S.M.; Johnson, R.W. Increased interleukin-6 expression by microglia from brain of aged mice. J. Neuroimmunol., 1999, 93, 139-148.
168. Letiembre, M.; Hao, W.; Liu, Y.; Walter, S, Mihaljevic, I.; Rivest, S.; Hartmann, T.; Fassbender, K. Innate immune receptor expression in normal brain aging. Neuroscience, 2007, 146, 248-254.
169. Streit, W.J.; Sammons, N.W.; Kuhns, A.J.; Sparks D.L. Dystrophic microglia in the aging human brain. Glia, 2004, 45, 208-212.
170. Lopes, K.O.; Sparks D.L.; Streit W.J. Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia, 2008, 56, 1048-1060.
171. Conde, J.R.; Streit W.J. Microglia in the aging brain. J. Neuropathol. Exp. Neurol., 2006, 65, 199-203.
172. Streit, W.J.; Miller, K.R.; Lopes K.O.; Njie, E. Microglial degeneration in the aging brain--bad news for neurons? Front. Biosci., 2008, 13, 3423-3438.
173. Lawson L.J.; Perry V.H.; Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience, 1992, 48, 405-415.
174. Miller, K.R.; Streit, W.J. The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol., 2007, 3, 245-253.
175. Flanary, B.E.; Streit, W.J. Telomeres shorten with age in rat cerebellum and cortex in vivo. J. Anti Aging Med., 2003, 6, 299-308.
176. Ralay Ranaivo H.; Craft J.M.; Hu, W.; Guo, L.; Wing, L.K.; van Eldik, L.J.; Watterson, D.M. Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J. Neurosci., 2006, 26, 662-670.
177. McGeer, P.L.; Rogers, J.; McGeer, E.G. Inflammation, antiinflammatory agents and Alzheimer disease: the last 12 years. J. Alzheimers Dis., 2006, 9, 271-276.
178. Gowing, G.; Philips, T.; Van Wijmeersch, B.; Audet, J.N.; Dewil, M.; Van Den Bosch, L.; Billiau, A.D.; Robberecht, W.; Julien, J.P. Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J. Neurosci., 2008, 41, 10234-10244.
179. Grathwohl, S.A.; Kälin, R.E.; Bolmont, T.; Prokop, S.; Winkelmann, G.; Kaeser, S.A.; Odenthal, J.; Radde, R.; Eldh, T.; Gandy, S.; Aguzzi, A.; Staufenbiel, M.; Mathews, P.M.; Wolburg, H.; Heppner, F.L.; Jucker, M. Formation and maintenance of Alzheimer's disease betaamyloid plaques in the absence of microglia. Nat. Neurosci., 2009, 12, 1361-1363.