The brain's best friend: Microglial neurotoxicity revisited

Frontiers in Cellular Neuroscience

Volumn , Issue APR, 2013, Pages

  Hellwig, Sabine ^a   Heinrich, Annette ^a   Biber, Knut ^a,b  

^a UNIVERSITY OF FREIBURG   (Germany)

^b UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

Author keywords

CX3CR1; Innate immunity; Microglia; Microglia depletion; Mouse models; Neuroprotection

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; CD11B ANTIGEN; CD200 RECEPTOR; CD45 ANTIGEN; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CX3CR1; CLODRONIC ACID; COPPER ZINC SUPEROXIDE DISMUTASE; CUPRIZONE; GAMMA INTERFERON; GANCICLOVIR; MEMBRANE RECEPTOR; METHAMPHETAMINE; MINOCYCLINE; N METHYL DEXTRO ASPARTIC ACID; PILOCARPINE; TRIFLUSAL; TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; UNCLASSIFIED DRUG;

ALLERGIC ENCEPHALOMYELITIS; AMYOTROPHIC LATERAL SCLEROSIS; CELL ACTIVATION; CELL ACTIVITY; CELL DIFFERENTIATION; CELL FUNCTION; CELL POPULATION; CELL STRUCTURE; CELL SURVIVAL; CEREBROVASCULAR ACCIDENT; CYTOLOGY; DEPLETION; ENZYME INHIBITION; EXCITOTOXICITY; GENE; GENE MUTATION; HUMAN; MACROPHAGE; MICROGLIA; MONOCYTE; NERVE CELL LESION; NEUROPATHIC PAIN; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; PARKINSON DISEASE; PROTEIN EXPRESSION; REVIEW; SOD1 GENE;

EID: 84878036641     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2013.00071     Document Type: Review

References (165)

1. Abbadie, C., Lindia, J. A., Cumiskey, A. M., Peterson, L. B., Mudgett, J. S., Bayne, E. K., et al. (2003). Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl. Acad. Sci. U.S.A. 100, 7947-7952.
2. Acarin, L., Gonzalez, B., Castellano, B., and Castro, A. J. (1996). Microglial response to N -methyl-D-aspartatemediated excitotoxicity in the immature rat brain. J. Comp. Neurol. 367, 361-374.
3. Aguzzi, A., Barres, B. A., and Bennett, M. L. (2013). Microglia: scapegoat, saboteur, or something else? Science 339, 156-161.
4. Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M., and Rossi, F. M. (2011). Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142-1149.
5. Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W., and Rossi, F. M. (2007). Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538-1543.
6. Allan, S. M., Tyrrell, P. J., and Rothwell, N. J. (2005). Interleukin-1 and neuronal injury. Nat. Rev. Immunol. 5, 629-640.
7. Alliot, F., Godin, I., and Pessac, B. (1999). Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145-152.
8. Beers, D. R., Henkel, J. S., Xiao, Q., Zhao, W., Wang, J., Yen, A. A., et al. (2006). Wild-type microglia extend survival in PU. 1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 103, 16021-16026.
9. Biber, K., Neumann, H., Inoue, K., and Boddeke, H. W. (2007). Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci. 30, 596-602.
10. Blais, V., and Rivest, S. (2004). Effects of TNF-alpha and IFN-gamma on nitric oxide-induced neurotoxicity in the mouse brain. J. Immunol. 172, 7043-7052.
11. Block, M. L., Zecca, L., and Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69.
12. Boillée, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., et al. (2006). Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392.
13. Boje, K. M., and Arora, P. K. (1992). Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 587, 250-256.
14. Boscia, F., Annunziato, L., and Taglialatela, M. (2006). Retigabine and flupirtine exert neuroprotective actions in organotypic hippocampal cultures. Neuropharmacology 51, 283-294.
15. Boucsein, C., Kettenmann, H., and Nolte, C. (2000). Electrophysiological properties of microglial cells in normal and pathologic rat brain slices. Eur. J. Neurosci. 12, 2049-2058.
16. Broderick, C., Hoek, R. M., Forrester, J. V., Liversidge, J., Sedgwick, J. D., and Dick, A. D. (2002). Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am. J. Pathol. 161, 1669-1677.
17. Buiting, A. M., and Van Rooijen, N. (1994). Liposome mediated depletion of macrophages: an approach for fundamental studies. J. Drug Target. 2, 357-362.
18. Burguillos, M. A., Deierborg, T., Kavanagh, E., Persson, A., Hajji, N., Garcia-Quintanilla, A., et al. (2011). Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319-324.
19. Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., et al. (2006). Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917-924.
20. Chao, C. C., Hu, S., Molitor, T. W., Shaskan, E. G., and Peterson, P. K. (1992). Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J. Immunol. 149, 2736-2741.
21. Cho, S. H., Sun, B., Zhou, Y., Kauppinen, T. M., Halabisky, B., Wes, P., et al. (2011). CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J. Biol. Chem. 286, 32713-32722.
22. Cipriani, R., Villa, P., Chece, G., Lauro, C., Paladini, A., Micotti, E., et al. (2011). CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J. Neurosci. 31, 16327-16335.
23. Clement, A. M., Nguyen, M. D., Roberts, E. A., Garcia, M. L., Boillée, S., Rule, M., et al. (2003). Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113-117.
24. Colonna, M. (2003). DAP12 signaling: from immune cells to bone modeling and brain myelination. J. Clin. Invest. 111, 313-314.
25. Colton, C. A. (2009). Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune. Pharmacol. 4, 399-418.
26. Coull, J. A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., et al. (2005). BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017-1021.
27. Cronberg, T., Jensen, K., Rytter, A., and Wieloch, T. (2005). Selective sparing of hippocampal CA3 cells following in vitro ischemia is due to selective inhibition by acidosis. Eur. J. Neurosci. 22, 310-316.
28. de Haas, A. H., Boddeke, H. W., and Biber, K. (2008). Regionspecific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 56, 888-894.
29. de Haas, A. H., Boddeke, H. W., Brouwer, N., and Biber, K. (2007). Optimized isolation enables ex vivo analysis of microglia from various central nervous system regions. Glia 55, 1374-1384.
30. Deng, Y. Y., Lu, J., Ling, E. A., and Kaur, C. (2009). Monocyte chemoattractant protein-1 (MCP-1) produced via NF-kappaB signaling pathway mediates migration of amoeboid microglia in the periventricular white matter in hypoxic neonatal rats. Glia 57, 604-621.
31. Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B., Guyenet, P. G., et al. (2012). Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105-109.
32. Dimitrijevic, O. B., Stamatovic, S. M., Keep, R. F., and Andjelkovic, A. V. (2007). Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38, 1345-1353.
33. Drabek, T., Janata, A., Jackson, E. K., End, B., Stezoski, J., Vagni, V. A., et al. (2012). Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats. Resuscitation 83, 517-526.
34. Duffield, J. S., Forbes, S. J., Constandinou, C. M., Clay, S., Partolina, M., Vuthoori, S., et al. (2005). Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56-65.
35. Dunston, C. R., Griffiths, H. R., Lambert, P. A., Staddon, S., and Vernallis, A. B. (2011). Proteomic analysis of the anti-inflammatory action of minocycline. Proteomics 11, 42-51.
36. El Khoury, J., Toft, M., Hickman, S. E., Means, T. K., Terada, K., Geula, C., et al. (2007). Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432-438.
37. Falsig, J., Julius, C., Margalith, I., Schwarz, P., Heppner, F. L., and Aguzzi, A. (2008). A versatile prion replication assay in organotypic brain slices. Nat. Neurosci. 11, 109-117.
38. Fan, L. W., Pang, Y., Lin, S., Rhodes, P. G., and Cai, Z. (2005). Minocycline attenuates lipopolysaccharideinduced white matter injury in the neonatal rat brain. Neuroscience 133, 159-168.
39. Faustino, J. V., Wang, X., Johnson, C. E., Klibanov, A., Derugin, N., Wendland, M. F., et al. (2011). Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J. Neurosci. 31, 12992-13001.
40. Fendrick, S. E., Miller, K. R., and Streit, W. J. (2005). Minocycline does not inhibit microglia proliferation or neuronal regeneration in the facial nucleus following crush injury. Neurosci. Lett. 385, 220-223.
41. Fernández-López, D., Faustino, J., Derugin, N., Wendland, M., Lizasoain, I., Moro, M. A., et al. (2012). Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke. Neuroscience 207, 307-315.
42. Frotscher, M., Zafirov, S., and Heimrich, B. (1995). Development of identified neuronal types and of specific synaptic connections in slice cultures of rat hippocampus. Prog. Neurobiol. 45, 17-28.
43. Gao, H. M., Zhou, H., Zhang, F., Wilson, B. C., Kam, W., and Hong, J. S. (2011). HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J. Neurosci. 31, 1081-1092.
44. Gee, C. E., Benquet, P., Raineteau, O., Rietschin, L., Kirbach, S. W., and Gerber, U. (2006). NMDA receptors and the differential ischemic vulnerability of hippocampal neurons. Eur. J. Neurosci. 23, 2595-2603.
45. Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., et al. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841-845.
46. Gordon, S. (2002). Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927-930.
47. Gordon, S. (2003). Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23-35.
48. Gordon, S., and Mantovani, A. (2011). Diversity and plasticity of mononuclear phagocytes. Eur. J. Immunol. 41, 2470-2472.
49. Gowing, G., Philips, T., Van Wijmeersch, B., Audet, J. N., Dewil, M., Van Den Bosch, L., et al. (2008). Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J. Neurosci. 28, 10234-10244.
50. Gowing, G., Vallières, L., and Julien, J. P. (2006). Mouse model for ablation of proliferating microglia in acute CNS injuries. Glia 53, 331-337.
51. Graeber, M. B. (2010). Changing face of microglia. Science 330, 783-788.
52. Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., et al. (2009). Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361-1363.
53. Hailer, N. P., Jarhult, J. D., and Nitsch, R. (1996). Resting microglial cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia 18, 319-331.
54. Hanisch, U. K., and Kettenmann, H. (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387-1394.
55. Hashimoto, K., and Ishima, T. (2010). A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation [corrected] factor eIF4AI. PLoS ONE 5:e15430. doi: 10.1371/journal.pone.0015430
56. He, Y., Appel, S., and Le, W. (2001). Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res. 909, 187-193.
57. Heppner, F. L., Greter, M., Marino, D., Falsig, J., Raivich, G., Hövelmeyer, N., et al. (2005). Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146-152.
58. Heppner, F. L., Skutella, T., Hailer, N. P., Haas, D., and Nitsch, R. (1998). Activated microglial cells migrate towards sites of excitotoxic neuronal injury inside organotypic hippocampal slice cultures. Eur. J. Neurosci. 10, 3284-3290.
59. Herbomel, P., Thisse, B., and Thisse, C. (2001). Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptordependent invasive process. Dev. Biol. 238, 274-288.
60. Hoek, R. M., Ruuls, S. R., Murphy, C. A., Wright, G. J., Goddard, R., Zurawski, S. M., et al. (2000). Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768-1771.
61. Horn, M., and Schlote, W. (1992). Delayed neuronal death, and delayed neuronal recovery in the human brain following global ischemia. Acta Neuropathol. 85, 79-87.
62. Huang, W. C., Qiao, Y., Xu, L., Kacimi, R., Sun, X., Giffard, R. G., et al. (2010). Direct protection of cultured neurons from ischemia-like injury by minocycline. Anat. Cell Biol. 43, 325-331.
63. Hughes, E. H., Schlichtenbrede, F. C., Murphy, C. C., Broderick, C., van Rooijen, N., Ali, R. R., et al. (2004). Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism. Exp. Eye Res. 78, 1077-1084.
64. Hughes, P. M., Botham, M. S., Frentzel, S., Mir, A., and Perry, V. H. (2002). Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia 37, 314-327.
65. Hulshof, S., van Haastert, E. S., Kuipers, H. F., van den Elsen, P. J., De Groot, C. J., van der Valk, P., et al. (2003). CX3CL1 and CX3CR1 expression in human brain tissue: noninflammatory control versus multiple sclerosis. J. Neuropathol. Exp. Neurol. 62, 899-907.
66. Hunter, C. L., Bachman, D., and Granholm, A. C. (2004). Minocycline prevents cholinergic loss in a mouse model of Down's syndrome. Ann. Neurol. 56, 675-688.
67. Jung, H., Bhangoo, S., Banisadr, G., Freitag, C., Ren, D., White, F. A., et al. (2009). Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. J. Neurosci. 29, 8051-8062.
68. Jung, S., and Schwartz, M. (2012). Non-identical twins - microglia and monocyte-derived macrophages in acute injury and autoimmune inflammation. Front. Immunol. 3:89. doi: 10.3389/fimmu.2012.00089
69. Jung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A., et al. (2000). Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106-4114.
70. Kang, J., and Rivest, S. (2007). MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis. J. Cell Biol. 179, 1219-1230.
71. Kettenmann, H., Hanisch, U. K., Noda, M., and Verkhratsky, A. (2011). Physiology of microglia. Physiol. Rev. 91, 461-553.
72. Kettenmann, H., Kirchhoff, F., and Verkhratsky, A. (2013). Microglia: new roles for the synaptic stripper. Neuron 77, 10-18.
73. Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., et al. (2013). Microglia emerge from erythromyeloid precursors via Pu.1-and Irf8-dependent pathways. Nat. Neurosci. 16, 273-280.
74. Kim, S. U., and de Vellis, J. (2005). Microglia in health and disease. J. Neurosci. Res. 81, 302-313.
75. Kim, W. G., Mohney, R. P., Wilson, B., Jeohn, G. H., Liu, B., and Hong, J. S. (2000). Regional difference in susceptibility to lipopolysaccharideinduced neurotoxicity in the rat brain: role of microglia. J. Neurosci. 20, 6309-6316.
76. Kirino, T., and Sano, K. (1984). Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol. 62, 201-208.
77. Kohl, A., Dehghani, F., Korf, H. W., and Hailer, N. P. (2003). The bisphosphonate clodronate depletes microglial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp. Neurol. 181, 1-11.
78. Köhl, J. (2006). Self, non-self, and danger: a complementary view. Adv. Exp. Med. Biol. 586, 71-94.
79. Koning, N., Bö, L., Hoek, R. M., and Huitinga, I. (2007). Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann. Neurol. 62, 504-514.
80. Koning, N., Swaab, D. F., Hoek, R. M., and Huitinga, I. (2009). Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions. J. Neuropathol. Exp. Neurol. 68, 159-167.
81. Kriz, J., Nguyen, M. D., and Julien, J. P. (2002). Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 10, 268-278.
82. Lalancette-Hébert, M., Gowing, G., Simard, A., Weng, Y. C., and Kriz, J. (2007). Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci. 27, 2596-2605.
83. Lauro, C., Cipriani, R., Catalano, M., Trettel, F., Chece, G., Brusadin, V., et al. (2010). Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Gluinduced death. Neuropsychopharmacology 35, 1550-1559.
84. Ledeboer, A., Sloane, E. M., Milligan, E. D., Frank, M. G., Mahony, J. H., Maier, S. F., et al. (2005). Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115, 71-83.
85. Lehnardt, S., Schott, E., Trimbuch, T., Laubisch, D., Krueger, C., Wulczyn, G., et al. (2008). A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J. Neurosci. 28, 2320-2331.
86. Levesque, S., Wilson, B., Gregoria, V., Thorpe, L. B., Dallas, S., Polikov, V. S., et al. (2010). Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity. Brain 133(Pt 3), 808-821.
87. Lindia, J. A., McGowan, E., Jochnowitz, N., and Abbadie, C. (2005). Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. J. Pain 6, 434-438.
88. Linnartz, B., Wang, Y., and Neumann, H. (2010). Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation. Int. J. Alzheimers Dis. 2010, pii: 587463.
89. Lino, M. M., Schneider, C., and Caroni, P. (2002). Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22, 4825-4832.
90. Lobsiger, C. S., and Cleveland, D. W. (2007). Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat. Neurosci. 10, 1355-1360.
91. Martinez, F. O., Sica, A., Mantovani, A., and Locati, M. (2008). Macrophage activation and polarization. Front. Biosci. 13, 453-461.
92. Matzinger, P. (2002). An innate sense of danger. Ann. N. Y. Acad. Sci. 961, 341-342.
93. Medzhitov, R. (2010). Innate immunity: quo vadis? Nat. Immunol. 11, 551-553.
94. Melief, J., Koning, N., Schuurman, K. G., Van De Garde, M. D., Smolders, J., Hoek, R. M., et al. (2012). Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia 60, 1506-1517.
95. Mika, J., Osikowicz, M., Makuch, W., and Przewlocka, B. (2007). Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur. J. Pharmacol. 560, 142-149.
96. Mildner, A., Mack, M., Schmidt, H., Brück, W., Djukic, M., Zabel, M. D., et al. (2009). CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132(Pt 9), 2487-2500.
97. Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U. K., Mack, M., et al. (2007). Microglia in the adult brain arise from Ly6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544-1553.
98. Mirrione, M. M., Konomos, D. K., Gravanis, I., Dewey, S. L., Aguzzi, A., Heppner, F. L., et al. (2010). Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice. Neurobiol. Dis. 39, 85-97.
99. Mizutani, M., Pino, P. A., Saederup, N., Charo, I. F., Ransohoff, R. M., and Cardona, A. E. (2012). The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J. Immunol. 188, 29-36.
100. Montero Domínguez, M., González, B., and Zimmer, J. (2009). Neuroprotective effects of the anti-inflammatory compound triflusal on ischemia-like neurodegeneration in mouse hippocampal slice cultures occur independent of microglia. Exp. Neurol. 218, 11-23.
101. Montero, M., Gonzalez, B., and Zimmer, J. (2009). Immunotoxic depletion of microglia in mouse hippocampal slice cultures enhances ischemia-like neurodegeneration. Brain Res. 1291, 140-152.
102. Morganti, J. M., Nash, K. R., Grimmig, B. A., Ranjit, S., Small, B., Bickford, P. C., et al. (2012). The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson's disease. J. Neurosci. 32, 14592-14601.
103. Mosser, D. M., and Edwards, J. P. (2008). Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958-969.
104. Nadeau, S., and Rivest, S. (2002). Endotoxemia prevents the cerebral inflammatory wave induced by intraparenchymal lipopolysaccharide injection: role of glucocorticoids and CD14. J. Immunol. 169, 3370-3381.
105. Nadeau, S., and Rivest, S. (2003). Glucocorticoids play a fundamental role in protecting the brain during innate immune response. J. Neurosci. 23, 5536-5544.
106. Neumann, H., and Wekerle, H. (2013). Brain microglia: watchdogs with pedigree. Nat. Neurosci. 16, 253-255.
107. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318.
108. O'Callaghan, J. P., Sriram, K., and Miller, D. B. (2008). Defining neuroinflammation. Ann. N. Y. Acad. Sci. 1139, 318-330.
109. Olah, M., Amor, S., Brouwer, N., Vinet, J., Eggen, B., Biber, K., et al. (2012). Identification of a microglia phenotype supportive of remyelination. Glia 60, 306-321.
110. Osikowicz, M., Skup, M., Mika, J., Makuch, W., Czarkowska-Bauch, J., and Przewlocka, B. (2009). Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5, and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain. Pain 147, 175-186.
111. Ossola, B., Lantto, T. A., Puttonen, K. A., Tuominen, R. K., Raasmaja, A., and Männistö, P. T. (2012). Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and - independent programmed cell death. J. Neurosci. Res. 90, 682-690.
112. Pabon, M. M., Bachstetter, A. D., Hudson, C. E., Gemma, C., and Bickford, P. C. (2011). CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. J. Neuroinflammation 8, 9.
113. Pais, T. F., Figueiredo, C., Peixoto, R., Braz, M. H., and Chatterjee, S. (2008). Necrotic neurons enhance microglial neurotoxicity through induction of glutaminase by a MyD88-dependent pathway. J. Neuroinflammation 5, 43.
114. Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., et al. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456-1458.
115. Parkhurst, C. N., and Gan, W. B. (2010). Microglia dynamics and function in the CNS. Curr. Opin. Neurobiol. 20, 595-600.
116. Polazzi, E., and Monti, B. (2010). Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog. Neurobiol. 92, 293-315.
117. Pramatarova, A., Laganière, J., Roussel, J., Brisebois, K., and Rouleau, G. A. (2001). Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369-3374.
118. Prinz, M., and Mildner, A. (2011). Microglia in the CNS: immigrants from another world. Glia 59, 177-187.
119. Prinz, M., and Priller, J. (2010). Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J. Neuroimmunol 224, 80-84.
120. Prinz, M., Priller, J., Sisodia, S. S., and Ransohoff, R. M. (2011). Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227-1235.
121. Raber, J., Allen, A. R., Rosi, S., Sharma, S., Dayger, C., Davis, M. J., et al. (2013). Effects of 56Fe radiation on hippocampal function in mice deficient in chemokine receptor 2 (CCR2). Behav. Brain Res. 246, 69-75.
122. Raghavendra, V., Tanga, F., and DeLeo, J. A. (2003). Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624-630.
123. Ransohoff, R. M., and Cardona, A. E. (2010). The myeloid cells of the central nervous system parenchyma. Nature 468, 253-262.
124. Ransohoff, R. M., and Perry, V. H. (2009). Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145.
125. Ransohoff, R. M., and Prinz, M. (2013). Editors' preface: microglia a new era dawns. Glia 61, 1-2.
126. Remington, L. T., Babcock, A. A., Zehntner, S. P., and Owens, T. (2007). Microglial recruitment, activation, and proliferation in response to primary demyelination. Am. J. Pathol. 170, 1713-1724.
127. Saederup, N., Cardona, A. E., Croft, K., Mizutani, M., Cotleur, A. C., Tsou, C. L., et al. (2010). Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knockin mice. PLoS ONE 5:e13693. doi: 10.1371/journal.pone.0013693
128. Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., et al. (2012). Microglia sculpt postnatal neural circuits in an activity and complementdependent manner. Neuron 74, 691-705.
129. Schauwecker, P. E. (2002). Modulation of cell death by mouse genotype: differential vulnerability to excitatory amino acid-induced lesions. Exp. Neurol. 178, 219-235.
130. Schildknecht, S., Pape, R., Müller, N., Robotta, M., Marquardt, A., Bürkle, A., et al. (2011). Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite. J. Biol. Chem. 286, 4991-5002.
131. Schilling, M., Strecker, J. K., Ringelstein, E. B., Schäbitz, W. R., and Kiefer, R. (2009a). The role of CC chemokine receptor 2 on microglia activation and blood-borne cell recruitment after transient focal cerebral ischemia in mice. Brain Res. 1289, 79-84.
132. Schilling, M., Strecker, J. K., Schäbitz, W. R., Ringelstein, E. B., and Kiefer, R. (2009b). Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience 161, 806-812.
133. Schmid, C. D., Melchior, B., Masek, K., Puntambekar, S. S., Danielson, P. E., Lo, D. D., et al. (2009). Differential gene expression in LPS/IFNgamma activated microglia, and macrophages: in vitro versus in vivo. J. Neurochem. 109(Suppl. 1), 117-125.
134. Sedgwick, J. D., Ford, A. L., Foulcher, E., and 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.
135. Sierra, A., Encinas, J. M., Deudero, J. J., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., et al. (2010). Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483-495.
136. Sorokin, S. P., Hoyt, R. F. Jr., Blunt, D. G., and McNelly, N. A. (1992). Macrophage development: II. Early ontogeny of macrophage populations in brain, liver, and lungs of rat embryos as revealed by a lectin marker. Anat. Rec. 232, 527-550.
137. Szeto, G. L., Pomerantz, J. L., Graham, D. R., and Clements, J. E. (2011). Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J. Biol. Chem. 286, 11275-11282.
138. Takahashi, K., Rochford, C. D., and Neumann, H. (2005). Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647-657.
139. Tarozzo, G., Campanella, M., Ghiani, M., Bulfone, A., and Beltramo, M. (2002). Expression of fractalkine, and its receptor, CX3CR1, in response to ischaemia-reperfusion brain injury in the rat. Eur. J. Neurosci. 15, 1663-1668.
140. Tikka, T., Fiebich, B. L., Goldsteins, G., Keinanen, R., and Koistinaho, J. (2001). Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J. Neurosci. 21, 2580-2588.
141. Tremblay, M. È., Lowery, R. L., and Majewska, A. K. (2010). Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8:e1000527. doi: 10.1371/journal.pbio.1000527
142. Tremblay, M. È., Stevens, B., Sierra, A., Wake, H., Bessis, A., and Nimmerjahn, A. (2011). The role of microglia in the healthy brain. J. Neurosci. 31, 16064-16069.
143. Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M. W., et al. (2003). P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778-783.
144. Tsuda, M., Beggs, S., Salter, M. W., and Inoue, K. (2013). Microglia and intractable chronic pain. Glia 61, 55-61.
145. Ueno, M., Fujita, Y., Tanaka, T., Nakamura, Y., Kikuta, J., Ishii, M., et al. (2013). Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16, 543-551.
146. Ulmann, L., Hatcher, J. P., Hughes, J. P., Chaumont, S., Green, P. J., Conquet, F., et al. (2008). Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J. Neurosci. 28, 11263-11268.
147. van Weering, H. R., Boddeke, H. W., Vinet, J., Brouwer, N., de Haas, A. H., van Rooijen, N., et al. (2011). CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus. Hippocampus 21, 220-232.
148. Varvel, N. H., Grathwohl, S. A., Baumann, F., Liebig, C., Bosch, A., Brawek, B., et al. (2012). Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl. Acad. Sci. U.S.A. 109, 18150-18155.
149. Vinet, J., Weering, H. R., Heinrich, A., Kälin, R. E., Wegner, A., Brouwer, N., et al. (2012). Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J. Neuroinflammation 9, 27.
150. Vornov, J. J., Tasker, R. C., and Coyle, J. T. (1991). Direct observation of the agonist-specific regional vulnerability to glutamate, NMDA, and kainate neurotoxicity in organotypic hippocampal cultures. Exp. Neurol. 114, 11-22.
151. Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S., and Nabekura, J. (2009). Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974-3980.
152. Walker, D. G., Dalsing-Hernandez, J. E., Campbell, N. A., and Lue, L. F. (2009). Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation. Exp. Neurol. 215, 5-19.
153. Walker, D. G., and Lue, L. F. (2005). Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases. J. Neurosci. Res. 81, 412-425.
154. Wolf, Y., Yona, S., Kim, K. W., and Jung, S. (2013). Microglia, seen from the CX3CR1 angle. Front. Cell. Neurosci. 7:26. doi: 10.3389/fncel.2013.00026
155. Won, S. J., Ko, H. W., Kim, E. Y., Park, E. C., Huh, K., Jung, N. P., et al. (1999). Nuclear factor kappa B-mediated kainate neurotoxicity in the rat and hamster hippocampus. Neuroscience 94, 83-91.
156. Wynne, A. M., Henry, C. J., Huang, Y., Cleland, A., and Godbout, J. P. (2010). Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav. Immun. 24, 1190-1201.
157. Xie, Z., Smith, C. J., and Van Eldik, L. J. (2004). Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38. Glia 45, 170-179.
158. Xu, Y., Zeng, K., Han, Y., Wang, L., Chen, D., Xi, Z., et al. (2012). Altered expression of CX3CL1 in patients with epilepsy and in a rat model. Am. J. Pathol. 180, 1950-1962.
159. Yao, Y., and Tsirka, S. E. (2012). The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage. Glia 60, 908-918.
160. Yi, M. H., Zhang, E., Kang, J. W., Shin, Y. N., Byun, J. Y., Oh, S. H., et al. (2012). Expression of CD200 in alternative activation of microglia following an excitotoxic lesion in the mouse hippocampus. Brain Res. 1481, 90-96.
161. Yona, S., Kim, K. W., Wolf, Y., Mildner, A., Varol, D., Breker, M., et al. (2013). Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79-91.
162. Yong, V. W., and Rivest, S. (2009). Taking advantage of the systemic immune system to cure brain diseases. Neuron 64, 55-60.
163. Yrjänheikki, J., Keinänen, R., Pellikka, M., Hökfelt, T., and Koistinaho, J. (1998). Tetracyclines inhibit microglial activation, and are neuroprotective in global brain ischemia. Proc. Natl. Acad. Sci. U.S.A. 95, 15769-15774.
164. Zhang, J., Shi, X. Q., Echeverry, S., Mogil, J. S., De Koninck, Y., and Rivest, S. (2007). Expression of CCR2 in both resident and bone marrowderived microglia plays a critical role in neuropathic pain. J. Neurosci. 27, 12396-12406.
165. Zuurman, M. W., Heeroma, J., Brouwer, N., Boddeke, H. W., and Biber, K. (2003). LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo. Glia 41, 327-336.