Abstract
Microglia—the macrophage equivalent of the CNS—safeguards and supports neuronal functions. Threats to the CNS homeostasis can trigger a rapid transformation of these cells from a normally “resting” into alerted and “activated” states. Microglia primarily serves the tissue defence and protection when participating in mechanisms of innate and adaptive immunity. On the contrary, excessive acute or chronic microglial activation can provoke severe neuronal and glial damage by carrying or fuelling destructive cascades. Several factors and conditions have already been identified that maintain the resting phenotype or organize and control the activation process. Cells are thereby able to recognize a dangerous signal as well as to sense functional disturbance. Microglial activation is also proving a much more variable and adaptive process than previously noticed. Aiming at microglia as a therapeutic target, research may focus on intracellular pathways that are probably common to activation scenarios as triggered by various receptor systems. Certain signalling elements may have key roles in the cytosolic integration of sensory inputs and a conversion into programs of executive performance. As the integrative aspect of microglial activation becomes illuminated hope builds up also on strategies for selective interference with harmful outcomes in favour of the—phylogenetically approved—beneficial potential of these fascinating cells.
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REFERENCES
- Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G.M., Cooper, N.R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., Finch, C.E., Frautschy, S., Griffin, W.S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I.R., McGeer, P.L., O'Banion, M.K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., Van Muiswinkel, F.L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G., and Wyss-Coray, T. (2000). Inflammation and Alzheimer's disease. Neurobiol. Aging21:383–421. 
- Aloisi, F. (2001). Immune function of microglia. Glia 36:165–179. 
- Asensio, V.C., and Campbell, I.L. (1999). Chemokines in the CNS: Plurifunctional mediators in diverse states. tiTrends Neurosci. 22:504–512. 
- Beattie, M.S., Hermann, G.E., Rogers, R.C., and Bresnahan, J.C. (2002). Cell death in models of spinal cord injury. Prog. Brain Res. 137:37–47. 
- Besedovsky, H.O., and del Rey, A. (2001). Cytokines as mediators of central and peripheral immune-neuroendocrine interactions. In (R. Ader, D.L. Felten, and N. Cohen, eds.), Psychoneuroimmunology, Academic Press, San Diego, CA, pp. 1–17. 
- Bezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J., and Volterra, A. (2001). CXCR4-activated astrocyte glutamate release via TNFalpha: Amplification by microglia triggers neurotoxicity. Nat. Neurosci. 4:702–710. 
- Bezzi, P., and Volterra, A. (2001). A neuron-glia signalling network in the active brain. Curr. Opin. Neurobiol. 11:387–394. 
- Biber, K., Sauter, A., Brouwer, N., Copray, S.C., and Boddeke, H.W. (2001). Ischemia-induced neuronal expression of the microglia attracting chemokine secondary lymphoid-tissue Chemokine (SLC). Glia 34:121–133. 
- Biber, K., Zuurman, M.W., Dijkstra, I.M., and Boddeke, H.W.G.M. (2002). Chemokines in the brain: Neuroim-munology and beyond. Curr. Opin. Pharmacol. 2:63–68. 
- Boucsein, C., Zacharias, R., Farber, K., Pavlovic, S., Hanisch, U.K., and Kettenmann, H. (2003). Purinergic receptors on microglial cells: Functional expression in acute brain slices and modulation of microglial activation in vitro. Eur. J. Neurosci. 17:2267–2276. 
- Brown, G.C., and Bal-Price, A. (2003). Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol. Neurobiol. 27:325–355. 
- Butterworth, R.F. (1998). Pathogenesis of acute hepatic encephalopathy. Digestion 59(Suppl. 2):16–21. 
- Butterworth, R.F. (2001). Neurotransmitter dysfunction in hepatic encephalopathy: New approaches and new findings. Metab. Brain Dis. 16:55–65. 
- Coughlin, S.R. (2000). Thrombin signalling and protease-activated receptors. Nature 407:258–264. 
- Cuadros, M.A., and Navascues, J. (1998). The origin and differentiation of microglial cells during development. Prog. Neurobiol. 56:173–189 
- Cuadros, M.A., and Navascues, J. (2001). Early origin and colonization of the developing central nervous system by microglial precursors. Prog. Brain Res. 132:51–59. 
- de Gans, J., and van de Beek, D. (2002). Dexamethasone in adults with bacterial meningitis. N. Engl. J. Med. 347:1549–1556. 
- Dong, Y., and Benveniste, E.N. (2001). Immune function of astrocytes. Glia 36:180–190. 
- Draheim, H.J., Prinz, M., Weber, J.R., Weiser, T., Kettenmann, H., and Hanisch, U.K. (1999). Induction of K channels in mouse brain microglia: Cells acquire responsiveness to pneumococcal cell wall components during late development. Neuroscience 89:1379–1390. 
- Eikelenboom, P., Bate, C., Van Gool, W.A., Hoozemans, J.J., Rozemuller, J.M., Veerhuis, R., and Williams, A. (2002). Neuroinflammation in Alzheimer's disease and prion disease. Glia 40:232–239. 
- Elkabes, S., DiCicco, B.E., and Black, I.B. (1996). Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci. 16:2508–2521. 
- Emsley, H.C., and Tyrrell, P.J. (2002). Inflammation and infection in clinical stroke. J. Cereb. Blood Flow Metab. 22:1399–1419. 
- Garden, G.A. (2002). Microglia in human immunodeficiency virus-associated neurodegeneration. Glia 40:240–251. 
- Gingrich, M.B., and Traynelis, S.F. (2000). Serine proteases and brain damage—is there a link? Trends Neurosci. 23:399–407. 
- Giulian, D. (1995). Microglia and neuronal dysfunction. In (H. Kettenmann, and B.R. Ransom, eds.), Neuroglia, Oxford University Press, New York, pp. 671–684. 
- Hanisch, U.K. (2001a). Effects of interleukin-2 and interferons on the nervous system. In (R. Ader, D.L. Felten, and N. Cohen, eds.), Psychoneuroimmunology, Academic Press, San Diego, CA, pp. 585–631. 
- Hanisch, U.K. (2001b). Microglia as a source and target of cytokine activities in the brain. In (W.J. Streit, ed.), Microglia in the Degenerating and Regenerating CNS, Springer-Verlag, New York, pp. 79–124. 
- Hanisch, U.K. (2002). Microglia as a source and target of cytokines. Glia 40:140–155. 
- Hanisch, U.K., Kohsaka, S., and M¨ oller, T. (2002a). Editorial. Glia 40:131–132. 
- Hanisch, U.K., Kohsaka, S., and M¨ oller, T., guest eds. (2002b). Microglia, Special issue. Glia 40(2):131–269. 
- Hanisch, U.K., Prinz, M., Angstwurm, K., H¨ ausler, K.G., Kann, O., Kettenmann, H., and Weber, J.R. (2001). The protein tyrosine kinase inhibitor AG126 prevents the massive microglial cytokine induction by pneumococcal cell walls. Eur. J. Immunol. 31:2104–2115. 
- Harrison, J.K., Jiang, Y., Chen, S., Xia, Y., Maciejewski, D., McNamara, R.K., Streit, W.J., Salafranca, M.N., Adhikari, S., Thompson, D.A., Botti, P., Bacon, K.B., and Feng, L. (1998). Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. U. S. A. 95:10896–10901. 
- H¨ ausler, K.G., Prinz, M., Nolte, C., Weber, J.R., Schumann, R.R., Kettenmann, H., and Hanisch, U.K. (2002). Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide-and pneumococcal cell wall-stimulated mouse microglia and macrophages. Eur. J. Neurosci. 16:2113–2122. 
- Heppner, F.L., Prinz, M., and Aguzzi, A. (2001). Pathogenesis of prion diseases: Possible implications of microglial cells. Prog. Brain Res. 132:737–750. 
- Hickey, W.F. (2001). Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118–124. 
- Hide, I., Tanaka, M., Inoue, A., Nakajima, K., Kohsaka, S., Inoue, K., and Nakata, Y. (2000). Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J. Neurochem. 75:965–972. 
- Hoek, R.M., Ruuls, S.R., Murphy, C.A., Wright, G.J., Goddard, R., Zurawski, S.M., Blom, B., Homola, M.E., Streit, W.J., Brown, M.H., Barclay, A.N., and Sedgwick, J.D. (2000). Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771. 
- Hoffmann, A., Kann, O., Ohlemeyer, C., Hanisch, U.K., and Kettenmann, H. (2003). Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): Suppression of receptor-evoked calcium signaling and control of release function. J. Neurosci. 23:4410–4419. 
- Honda, S., Sasaki, Y., Ohsawa, K., Imai, Y., Nakamura, Y., Inoue, K., and Kohsaka, S. (2001). Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J. Neurosci. 21:1975–1982. 
- Inoue, K. (2002). Microglial activation by purines and pyrimidines. Glia 40:156–163. 
- Johnson, S. (2001). Gradual micronutrient accumulation and depletion in Alzheimer's disease. Med. Hypotheses 56:595–597. 
- Kaul, M., Garden, G.A., and Lipton, S.A. (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994. 
- Kreutzberg, G.W. (1996). Microglia: A sensor for pathological events in the CNS. Trends Neurosci. 19:312–318. 
- Lassmann, H., Wekerle, H., Hickey, W.F., and Antel, J., guest eds. (2001). Neuroinflammation Special issue. Glia 36(2):117–243 
- Lazarini, F., Tham, T.N., Casanova, P., Arenzana-Seisdedos, F., and Dubois-Dalcq, M. (2003). Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia 42:139–148. 
- Lazarov, S.O., Rapalino, O., Agranov, G., and Schwartz, M. (1998). Restricted inflammatory reaction in the CNS: A key impediment to axonal regeneration? Mol. Med. Today 4:337–342. 
- Levitzki, A., and Gazit, A. (1995). Tyrosine kinase inhibition: An approach to drug development. Science 267:1782–1787. 
- Loddick, S.A., Liu, C., Takao, T., Hashimoto, K., and De Souza, E.B. (1998). Interleukin-1 receptors: Cloning studies and role in central nervous system disorders. Brain Res. Rev. 26:306–319. 
- McGeer, E.G., and McGeer, P.L. (1999). Brain inflammation in Alzheimer disease and the therapeutic implications. Curr. Pharm. Des. 5:821–836. 
- McGeer, P.L., and McGeer, E.G. (2001). Inflammation, autotoxicity and Alzheimer disease. Neurobiol. Aging 2 2:799–809. 
- McGeer, P.L., and McGeer, E.G. (2002). Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26:459–470. 
- McGeer, P.L., McGeer, E.G., and Yasojima, K. (2000). Alzheimer disease and neuroinflammation. J. Neural. Transm. Suppl. 59:53–57. 
- Mertsch, K., Hanisch, U.K., Kettenmann, H., and Schnitzer, J. (2001). Characterization of microglial cells and their response to stimulation in an organotypic retinal culture system. J. Comp. Neurol. 431:217–227. 
- Moalem, G., Gdalyahu, A., Shani, Y., Otten, U., Lazarovici, P., Cohen, I.R., and Schwartz, M. (2000). Production of neurotrophins by activated T cells: Implications for neuroprotective autoimmunity. J. Autoimmun. 15:331–345. 
- Nakajima, K., Tohyama, Y., Kohsaka, S., and Kurihara, T. (2001). Ability of rat microglia to uptake extracellular glutamate. Neurosci. Lett. 307:171–174. 
- Nakamura, Y. (2002). Regulating factors for microglial activation. Biol. Pharm. Bull. 25:945–953. 
- Nau, R., and Bruck, W. (2002). Neuronal injury in bacterial meningitis: Mechanisms and implications for therapy. Trends Neurosci. 25:38–45. 
- Nelson, P.T., Soma, L.A., and Lavi, E. (2002). Microglia in diseases of the central nervous system. Ann. Med. 34:491–500. 
- Neumann, H. (2001). Control of glial immune function by neurons. Glia 36:191–199. 
- Neumann, H., Boucraut, J., Hahnel, C., Misgeld, T., and Wekerle, H. (1996). Neuronal control of MHC class II inducibility in rat astrocytes and microglia. Eur. J. Neurosci. 8:2582–2590. 
- O'Keefe, G.M., Nguyen, V.T., and Benveniste, E.N. (2002). Regulation and function of class II major histocom-patibility complex, CD40, and B7 expression in macrophages and microglia: Implications in neurological diseases. J. Neurovirol. 8:496–512. 
- Orr, C.F., Rowe, D.B., and Halliday, G.M. (2002). An inflammatory reviewof Parkinson's disease. Prog. Neurobiol. 68:325–340. 
- O'Shea, J.J., Ma, A., and Lipsky, P. (2002). Cytokines and autoimmunity. Nat. Rev. Immunol. 2:37–45. 
- Perry, V.H., Newman, T.A., and Cunningham, C. (2003). The impact of systemic infection on the progression of neurodegenerative disease. Nat. Rev. Neurosci. 4:103–112. 
- Polazzi, E., and Contestabile, A. (2002). Reciprocal interactions between microglia and neurons: From survival to neuropathology. Rev. Neurosci. 13:221–242. 
- Polazzi, E., and Contestabile, A. (2003). Neuron-conditioned media differentially affect the survival of activated or unstimulated microglia: Evidence for neuronal control on apoptotic elimination of activated microglia. J. Neuropathol. Exp. Neurol. 62:351–362. 
- Priller, J., Flugel, A., Wehner, T., Boentert, M., Haas, C.A., Prinz, M., Fernandez-Klett, F., Prass, K., Bechmann, I., de Boer, B.A., Frotscher, M., Kreutzberg, G.W., Persons, D.A., and Dirnagl, U. (2001). Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7:1356–1361. 
- Prinz, M., Hausler, K.G., Kettenmann, H., and Hanisch, U. (2001). ß-adrenergic receptor stimulation selectively inhibits IL-12p40 release in microglia. Brain Res. 899:264–270. 
- Prinz, M., Kann, O., Draheim, H.J., Schumann, R.R., Kettenmann, H., Weber, J.R., and Hanisch, U.K. (1999). Microglial activation by components of Gram-positive and-negative bacteria: Distinct and common routes to the induction of ion channels and cytokines. J. Neuropathol. Exp. Neurol. 58:1078–1089. 
- Raber, J., Sorg, O., Horn, T.F., Yu, N., Koob, G.F., Campbell, I.L., and Bloom, F.E. (1998). Inflammatory cytokines: Putative regulators of neuronal and neuro-endocrine function. Brain Res. Rev. 26:320–326. 
- Raivich, G., Bohatschek, M., Kloss, C.U., Werner, A., Jones, L.L., and Kreutzberg, G.W. (1999). Neuroglial activation repertoire in the injured brain: Graded response, molecular mechanisms and cues to physiological function. Brain Res. Rev. 30:77–105. 
- Rao, K.V., and Norenberg, M.D. (2001). Cerebral energy metabolism in hepatic encephalopathy and hyperam-monemia. Metab. Brain Dis. 16:67–78 
- Rezaie, P., and Male, D. (2002). Mesoglia & microglia—A historical review of the concept of mononuclear phagocytes within the central nervous system. J. Hist. Neurosci. 11:325–374. 
- Rose, C. (2002). Increased extracellular brain glutamate in acute liver failure: Decreased uptake or increased release? Metab. Brain Dis. 17:251–261. 
- Rothwell, N., Allan, S., and Toulmond, S. (1997). Perspectives series: Cytokines and the brain. J. Clin. Invest. 100:2648–2652. 
- Sagara, Y., Ishige, K., Tsai, C., and Maher, P. (2002). Tyrphostins protect neuronal cells from oxidative stress. J. Biol. Chem. 277:36204–36215. 
- Schwartz, M. (2002). Autoimmunity as the body's defense mechanism against the enemy within: Development of therapeutic vaccines for neurodegenerative disorders. J. Neurovirol. 8:480–485. 
- Schwartz, M. (2003). Macrophages and microglia in central nervous system injury: Are they helpful or harmful? J. Cereb. Blood Flow Metab. 23:385–394. 
- Schwartz, M., and Cohen, I.R. (2000). Autoimmunity can benefit self-maintenance. Immunol. Today 21:265–268. 
- Seiler, N. (2002). Ammonia and Alzheimer's disease. Neurochem. Int. 41:189–207. 
- Stohwasser, R., Giesebrecht, J., Kraft, R., M¨ uller, E.-C., H¨ ausler, K.G., Kettenmann, H., Hanisch, U.K., and Kloetzel, P.-M. (2000). Biochemical analysis of proteasomes from microglia: Induction of immunoprotea-somes by interferon-ã and lipopolysaccharide. Glia 29:355–365. 
- Stoll, G., and Jander, S. (1999). The role of microglia and macrophages in the pathophysiology of the CNS. Prog. Neurobiol. 58:233–247. 
- Streit, W.J. (2000). Microglial response to brain injury: A brief synopsis. Toxicol. Pathol. 28:28–30. 
- Streit, W.J. (2002a). Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139. 
- Streit, W.J., ed. (2002b). Microglia in the Degenerating and Regenerating CNS, Springer-Verlag, New York. 
- Streit, W.J., Walter, S.A., and Pennel, N.A. (2000). Reactive microgliosis. Prog. Neurobiol. 57:563–581. 
- Takahashi, J.L., Giuliani, F., Power, C., Imai, Y., and Yong, V.W. (2003). Interleukin-1beta promotes oligoden-drocyte death through glutamate excitotoxicity. Ann. Neurol. 53:588–595. 
- Taylor, D.L., Diemel, L.T., and Pocock, J.M. (2003). Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity. J. Neurosci. 23:2150–2160. 
- Thomas, W.E. (1999). Brain macrophages: On the role of pericytes and perivascular cells. Brain Res. Brain Res.Rev. 31:42–57. 
- Vallat-Decouvelaere, A.V., Chretien, F., Gras, G., Le Pavec, G., Dormont, D., and Gray, F. (2003). Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia? J. Neuropathol. Exp. Neurol. 62:475–485. 
- van Rossum, D., and Hanisch, U.K. (in press). Microglia and the cerebral defence system. In (J.M. Delgado-Garcia, A. Privat, and T. Herdegen, eds.), Brain Damage and Repair: From Molecular Research to Clinical Therapy, Kluwer Academic, Dordrecht, pp. 181–202. 
- Wright, G.J., Puklavec, M.J., Willis, A.C., Hoek, R.M., Sedgwick, J.D., Brown, M.H., and Barclay, A.N. (2000). Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 13:233–242. 
- Yoles, E., Hauben, E., Palgi, O., Agranov, E., Gothilf, A., Cohen, A., Kuchroo, V., Cohen, I.R., Weiner, H., and Schwartz, M. (2001). Protective autoimmunity is a physiological response to CNS trauma. J. Neurosci. 21:3740–3748. 
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van Rossum, D., Hanisch, UK. Microglia. Metab Brain Dis 19, 393–411 (2004). https://doi.org/10.1023/B:MEBR.0000043984.73063.d8
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