Abstract
Following an eclipse of scientific inquiry regarding the biology of microglia that lasted 50 years, recognition toward the end of the 20th century of their neuropathogenic role in HIV-associated dementia and in neuroinflammatory/neurodegenerative diseases fueled a renaissance of interest in these resident macrophages of the brain parenchyma. Results of a large number of in vitro studies, using isolated microglial cells or glial/neuronal cell cultures, and parallel findings emerging from animal models and clinical studies have demonstrated that activated microglia produce a myriad of inflammatory mediators that both serve important defense functions against invading neurotropic pathogens and have been implicated in brain damage in infectious as well as neuroinflammatory/neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review provides a brief background regarding the physiological and pathophysiological roles of microglia and highlights current pharmacological approaches that target activated microglia with the goal of ameliorating infectious and neuroinflammatory/neurodegenerative diseases of the brain. Although this aspect of the field of neuroimmunopharmacology is in its infancy, it holds great promise for developing new treatments and prevention of diseases that are, in many cases, epidemic throughout the world.
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Adle-Biassette H, Chretien F, Wingertsmann L, Hery C, Ereau T, Scaravilli F, Tardieu M, Gray F (1999) Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage. Neuropathol Appl Neurobiol 25:123–133
Albright AV, Shieh JT, O'Connor MJ, Gonzalez-Scarano F (2000) Characterization of cultured microglia that can be infected by HIV-1. J Neurovirol 6(Suppl 1):S53–S60
Anthony DC, Ferguson B, Matyzak MK, Miller KM, Esiri MM, Perry VH (1997) Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathol Appl Neurobiol 23:406–415
Barcia C, Sanchez Bahillo A, Fernandez-Villalba E, Bautista V, Poza YPM, Fernandez-Barreiro A, Hirsch EC, Herrero MT (2004) Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure. Glia 46:402–409
Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A, Gonzalez-LaHoz J, Bouza E (1992) Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 326:668–672
Bi XL, Yang JY, Dong YX, Wang JM, Cui YH, Ikeshima T, Zhao YQ, Wu CF (2005) Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia. Int Immunopharmacol 5:185–193
Blasi E, Barluzzi R, Mazzolla R, Tancini B, Saleppico S, Puliti M, Pitzurra L, Bistoni F (1995) Role of nitric oxide and melanogenesis in the accomplishment of anticryptococcal activity by the BV-2 microglial cell line. J Neuroimmunol 58:111–116
Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98
Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31(1):149–60
Cacci E, Claasen JH, Kokaia Z (2005) Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res 80:789–797
Cagnin A, Myers R, Gunn RN, Lawrence AD, Stevens T, Kreutzberg GW, Jones T, Banati RB (2001) In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion. Brain 124:2014–2027
Chen MK, Baidoo K, Verina T, Guilarte TR (2004) Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain 127:1379–1392
Curto M, Reali C, Palmieri G, Scintu F, Schivo ML, Sogos V, Marcialis MA, Ennas MG, Schwarz H, Pozzi G, Gremo F (2004) Inhibition of cytokines expression in human microglia infected by virulent and non-virulent mycobacteria. Neurochem Int 44:381–392
del Rio-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and Cellular Pathology of the Nervous System. P.B. Hoebaer, New York, pp 483–534
Dheen ST, Jun Y, Yan Z, Tay SS, Ling EA (2005) Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia. Glia 50:21–31
Fan LW, Pang Y, Lin S, Tien LT, Ma T, Rhodes PG, Cai Z (2005) Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat. J Neurosci Res 82:71–82
Farber K, Kettenmann H (2005) Physiology of microglial cells. Brain Res Brain Res Rev 48:133–143
Farer LS, Lowell AM, Meador MP (1979) Extrapulmonary tuberculosis in the United States. Am J Epidemiol 109:205–217
Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995) Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38:755–762
Goldman D, Song X, Kitai R, Casadevall A, Zhao ML, Lee SC (2001) Cryptococcus neoformans induces macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta in human microglia: role of specific antibody and soluble capsular polysaccharide. Infect Immun 69:1808–1815
Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75:388–397
Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 193:279–290
Hirohata M, Ono K, Naiki H, Yamada M (2005) Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. Neuropharmacology 49:1088–99
Hoozemans JJ, O'Banion MK (2005) The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs. Curr Drug Targets CNS Neurol Disord 4:307–315
Jack C, Ruffini F, Bar-Or A, Antel JP (2005) Microglia and multiple sclerosis. J Neurosci Res 81:363–373
Lee SC, Liu W, Brosnan CF, Dickson DW (1992) Characterization of primary human fetal dissociated central nervous system cultures with an emphasis on microglia. Lab Invest 67:465–476
Lehrmann E, Kiefer R, Christensen T, Toyka KV, Zimmer J, Diemer NH, Hartung HP, Finsen B (1998) Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. Glia 24:437–448
Leonard JM, Des Prez RM (1990) Tuberculous meningitis. Infect Dis Clin North Am 4:769–787
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 102:9936–9941
Lindberg C, Crisby M, Winblad B, Schultzberg M (2005) Effects of statins on microglia. J Neurosci Res 82:10–19
Lipovsky MM, Gekker G, Anderson WR, Molitor TW, Peterson PK, Hoepelman AI (1997) Phagocytosis of nonopsonized Cryptococcus neoformans by swine microglia involves CD14 receptors. Clin Immunol Immunopathol 84:208–211
Lipovsky MM, Gekker G, Hu S, Hoepelman AI, Peterson PK (1998a) Morphine enhances complement receptor-mediated phagocytosis of Cryptococcus neoformans by human microglia. Clin Immunol Immunopathol 87:163–167
Lipovsky MM, Juliana AE, Gekker G, Hu S, Hoepelman AI, Peterson PK (1998b) Effect of cytokines on anticryptococcal activity of human microglial cells. Clin Diagn Lab Immunol 5:410–411
Lipton SA, Gendelman HE (1995) Seminars in medicine of the Beth Israel Hospital, Boston. Dementia associated with the acquired immunodeficiency syndrome. N Engl J Med 332:934–940
Liuzzi GM, Santacroce MP, Peumans WJ, Van Damme EJ, Dubois B, Opdenakker G, Riccio P (1999) Regulation of gelatinases in microglia and astrocyte cell cultures by plant lectins. Glia 27:53–61
Loscher W, Potschka H (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602
Matute C, Alberdi E, Ibarretxe G, Sanchez-Gomez MV (2002) Excitotoxicity in glial cells. Eur J Pharmacol 447: 239–246
Mazzolla R, Barluzzi R, Brozzetti A, Boelaert JR, Luna T, Saleppico S, Bistoni F, Blasi E (1997) Enhanced resistance to Cryptococcus neoformans infection induced by chloroquine in a murine model of meningoencephalitis. Antimicrob Agents Chemother 41:802–807
McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 21:195–218
Nakajima K, Kohsaka S (2002) Neuroprotective roles of microglia in the central nervous system. In: Microglia in the Regenerating and Degenerating CNS. Springer Verlag, New York
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318
O'Toole M, Janszen DB, Slonim DK, Reddy PS, Ellis DK, Legault HM, Hill AA, Whitley MZ, Mounts WM, Zuberek K, Immermann FW, Black RS, Dorner AJ (2005) Risk factors associated with beta-amyloid(1–42) immunotherapy in preimmunization gene expression patterns of blood cells. Arch Neurol 62:1531–1536
Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134:162–169
Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388
Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino G (2005) Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436:266–271
Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4:814–821
Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17:942–964
Rock RB, Hu S, Gekker G, Sheng WS, May B, Kapur V, Peterson PK (2005) Mycobacterium tuberculosis-induced cytokine and chemokine expression by human microglia and astrocytes: effects of dexamethasone. J Infect Dis 192:2054–2058
Rogers J, Lue LF (2001) Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int 39:333–340
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77
Si Q, Cosenza M, Kim MO, Zhao ML, Brownlee M, Goldstein H, Lee S (2004) A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia. J Neurovirol 10:284–292
Sowa G, Gekker G, Lipovsky MM, Hu S, Chao CC, Molitor TW, Peterson PK (1997) Inhibition of swine microglial cell phagocytosis of Cryptococcus neoformans by femtomolar concentrations of morphine. Biochem Pharmacol 53:823–828
Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139
Streit WJ (2005) Microglia and neuroprotection: implications for Alzheimer's disease. Brain Res Brain Res Rev 48:234–239
Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM (2004) Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311:1–7
Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15:601–609
Tzeng SF, Hsiao HY, Mak OT (2005) Prostaglandins and cyclooxygenases in glial cells during brain inflammation. Curr Drug Targets Inflamm Allergy 4:335–340
Weydt P, Moller T (2005) Neuroinflammation in the pathogenesis of amyotrophic lateral sclerosis. NeuroReport 16:527–531
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This work was supported, in part by U.S. Public Health Service grants DA04381, DA09783, and DA020398.
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Rock, R.B., Peterson, P.K. Microglia as a Pharmacological Target in Infectious and Inflammatory Diseases of the Brain. Jrnl NeuroImmune Pharm 1, 117–126 (2006). https://doi.org/10.1007/s11481-006-9012-8
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DOI: https://doi.org/10.1007/s11481-006-9012-8