The microglial

Journal of Neuroinflammation

Jun Tan¹  Veljko Nikolic¹  Terrence Town¹ 

[1] Neuroimmunology Laboratory, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida, 3515 E. Fletcher Ave., Tampa, FL 33613, USA

关键词: immunotherapy;    vaccine;    amyloid;    myelin;    encephalitis;    inflammation;    Toll-like receptor;    adaptive immunity;    innate immunity;    microglia;    brain;   

Others  :  1213659
DOI  :  10.1186/1742-2094-2-24

 received in 2005-10-24, accepted in 2005-10-31,  发布年份 2005

【 摘 要 】

Microglia are innate immune cells of myeloid origin that take up residence in the central nervous system (CNS) during embryogenesis. While classically regarded as macrophage-like cells, it is becoming increasingly clear that reactive microglia play more diverse roles in the CNS. Microglial "activation" is often used to refer to a single phenotype; however, in this review we consider that a continuum of microglial activation exists, with phagocytic response (innate activation) at one end and antigen presenting cell function (adaptive activation) at the other. Where activated microglia fall in this spectrum seems to be highly dependent on the type of stimulation provided. We begin by addressing the classical roles of peripheral innate immune cells including macrophages and dendritic cells, which seem to define the edges of this continuum. We then discuss various types of microglial stimulation, including Toll-like receptor engagement by pathogen-associated molecular patterns, microglial challenge with myelin epitopes or Alzheimer's β-amyloid in the presence or absence of CD40L co-stimulation, and Alzheimer disease "immunotherapy". Based on the wide spectrum of stimulus-specific microglial responses, we interpret these cells as immune cells that demonstrate remarkable plasticity following activation. This interpretation has relevance for neurodegenerative/neuroinflammatory diseases where reactive microglia play an etiological role; in particular viral/bacterial encephalitis, multiple sclerosis and Alzheimer disease.

【 授权许可】

   
2005 Town et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Pessac B, Godin I, Alliot F: [Microglia: origin and development]. Bull Acad Natl Med 2001, 185:337-346. discussion 346-337
• [2]Alliot F, Godin I, Pessac B: Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 1999, 117:145-152.
• [3]Eglitis MA, Mezey E: Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997, 94:4080-4085.
• [4]Brazelton TR, Rossi FM, Keshet GI, Blau HM: From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000, 290:1775-1779.
• [5]Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000, 290:1779-1782.
• [6]Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, et al.: Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 2001, 7:1356-1361.
• [7]Qureshi ST, Medzhitov R: Toll-like receptors and their role in experimental models of microbial infection. Genes Immun 2003, 4:87-94.
• [8]Yamamoto M, Takeda K, Akira S: TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 2004, 40:861-868.
• [9]Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S: A toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004, 303:1522-1526.
• [10]Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, et al.: Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 2004, 101:3516-3521.
• [11]Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197-216.
• [12]Medzhitov R, Janeway C Jr: The Toll receptor family and microbial recognition. Trends Microbiol 2000, 8:452-456.
• [13]Medzhitov R, Janeway CA Jr: How does the immune system distinguish self from nonself? Semin Immunol 2000, 12:185-188. discussion 257-344
• [14]Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002, 296:298-300.
• [15]Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004, 5:987-995.
• [16]Goldsby R, Kindt T, Osborne B, Kuby J: Mononuclear Phagocytes. In Immunology. 5th edition. Edited by Goldsby R. New York: Freeman and Co; 2002:38-19.
• [17]Adler H, Peterhans E, Jungi TW: Generation and functional characterization of bovine bone marrow-derived macrophages. Vet Immunol Immunopathol 1994, 41:211-227.
• [18]Blander JM, Medzhitov R: Regulation of phagosome maturation by signals from toll-like receptors. Science 2004, 304:1014-1018.
• [19]Forman HJ, Torres M: Redox signaling in macrophages. Mol Aspects Med 2001, 22:189-216.
• [20]Tsukada N, Miyagi K, Matsuda M, Yanagisawa N: Expression of Fc epsilon R2/CD23 and p55 IL-2R/CD25 on peripheral blood macrophages/monocytes in multiple sclerosis. J Neuroimmunol 1994, 55:127-133.
• [21]Blom AB, Radstake TR, Holthuysen AE, Sloetjes AW, Pesman GJ, Sweep FG, van de Loo FA, Joosten LA, Barrera P, van Lent PL, van den Berg WB: Increased expression of Fcgamma receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor alpha and matrix metalloproteinase. Arthritis Rheum 2003, 48:1002-1014.
• [22]Gregory CD, Devitt A: The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically? Immunology 2004, 113:1-14.
• [23]Fujiwara N, Kobayashi K: Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 2005, 4:281-286.
• [24]Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K: Immunobiology of dendritic cells. Annu Rev Immunol 2000, 18:767-811.
• [25]Shortman K, Liu YJ: Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002, 2:151-161.
• [26]Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G: Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002, 168:4531-4537.
• [27]Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A: Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001, 31:3388-3393.
• [28]Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ: Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001, 194:863-869.
• [29]Ito T, Amakawa R, Kaisho T, Hemmi H, Tajima K, Uehira K, Ozaki Y, Tomizawa H, Akira S, Fukuhara S: Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. J Exp Med 2002, 195:1507-1512.
• [30]Hemmi H, Kaisho T, Takeda K, Akira S: The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 2003, 170:3059-3064.
• [31]Olson JK, Miller SD: Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004, 173:3916-3924.
• [32]Bsibsi M, Ravid R, Gveric D, van Noort JM: Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 2002, 61:1013-1021.
• [33]Kielian T, Mayes P, Kielian M: Characterization of microglial responses to Staphylococcus aureus: effects on cytokine, costimulatory molecule, and Toll-like receptor expression. J Neuroimmunol 2002, 130:86-99.
• [34]Kielian T, Esen N, Bearden ED: Toll-like receptor 2 (TLR2) is pivotal for recognition of S. aureus peptidoglycan but not intact bacteria by microglia. Glia 2005, 49:567-576.
• [35]Iliev AI, Stringaris AK, Nau R, Neumann H: Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). Faseb J 2004, 18:412-414.
• [36]Dalpke AH, Schafer MK, Frey M, Zimmermann S, Tebbe J, Weihe E, Heeg K: Immunostimulatory CpG-DNA activates murine microglia. J Immunol 2002, 168:4854-4863.
• [37]Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T: The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002, 22:2478-2486.
• [38]Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 2003, 100:8514-8519.
• [39]Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001, 413:732-738.
• [40]Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP: TLR Signaling Tailors Innate Immune Responses in Human Microglia and Astrocytes. J Immunol 2005, 175:4320-4330.
• [41]Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA: Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 2004, 10:1366-1373.
• [42]Tan J, Town T, Paris D, Mori T, Suo ZM, Crawford F, Mattson MP, Flavell RA, Mullan M: Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 1999, 286:2352-2355.
• [43]Vogel SN, Fitzgerald KA, Fenton MJ: TLRs: differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv 2003, 3:466-477.
• [44]Hemmi H, Akira S: TLR signalling and the function of dendritic cells. Chem Immunol Allergy 2005, 86:120-135.
• [45]Olsson T: Cytokine-producing cells in experimental autoimmune encephalomyelitis and multiple sclerosis. Neurology 1995, 45:S11-15.
• [46]Swanborg RH: Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease. Clin Immunol Immunopathol 1995, 77:4-13.
• [47]Cornet A, Vizler C, Liblau R: [Experimental autoimmune encephalomyelitis]. Rev Neurol (Paris) 1998, 154:586-591.
• [48]van Kooten C, Banchereau J: CD40-CD40 ligand. J Leukoc Biol 2000, 67:2-17.
• [49]Grewal IS, Flavell RA: CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998, 16:111-135.
• [50]Nguyen VT, Walker WS, Benveniste EN: Post-transcriptional inhibition of CD40 gene expression in microglia by transforming growth factor-beta. Eur J Immunol 1998, 28:2537-2548.
• [51]Carson MJ, Reilly CR, Sutcliffe JG, Lo D: Mature microglia resemble immature antigen-presenting cells. Glia 1998, 22:72-85.
• [52]Havenith CE, Askew D, Walker WS: Mouse resident microglia: isolation and characterization of immunoregulatory properties with naive CD4+ and CD8+ T-cells. Glia 1998, 22:348-359.
• [53]Tan J, Town T, Paris D, Placzek A, Parker T, Crawford F, Yu H, Humphrey J, Mullan M: Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis. Journal of Neuroimmunology 1999, 97:77-85.
• [54]Gerritse K, Laman JD, Noelle RJ, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E: CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1996, 93:2499-2504.
• [55]Grewal IS, Foellmer HG, Grewal KD, Xu J, Hardardottir F, Baron JL, Janeway CA Jr, Flavell RA: Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 1996, 273:1864-1867.
• [56]Howard LM, Miga AJ, Vanderlugt CL, Dal Canto MC, Laman JD, Noelle RJ, Miller SD: Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. J Clin Invest 1999, 103:281-290.
• [57]Becher B, Durell BG, Miga AV, Hickey WF, Noelle RJ: The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J Exp Med 2001, 193:967-974.
• [58]Fischer HG, Reichmann G: Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 2001, 166:2717-2726.
• [59]McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD: Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 2005, 11:335-339.
• [60]Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, et al.: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383-421.
• [61]Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F: Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995, 374:647-650.
• [62]Barger SW, Harmon AD: Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 1997, 388:878-881.
• [63]McGeer EG, McGeer PL: The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol 1998, 33:371-378.
• [64]Stewart WF, Kawas C, Corrada M, Metter EJ: Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997, 48:626-632.
• [65]in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001, 345:1515-1521.
• [66]Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JC: Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 2002, 59:880-886.
• [67]Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, Goodman SN: Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology 2004, 23:159-169.
• [68]Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. Journal of Neuroscience 2000, 20:5709-5714.
• [69]Lim GP, Yang F, Chu T, Gahtan E, Ubeda O, Beech W, Overmier JB, Hsiao-Ashe K, Frautschy SA, Cole GM: Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiology of Aging 2001, 22:983-991.
• [70]Lim GP, Chu T, Yang FS, Beech W, Frautschy SA, Cole GM: The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. Journal of Neuroscience 2001, 21:8370-8377.
• [71]Paresce DM, Ghosh RN, Maxfield FR: Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 1996, 17:553-565.
• [72]Paresce DM, Chung H, Maxfield FR: Slow degradation of aggregates of the Alzheimer's disease amyloid beta-protein by microglial cells. J Biol Chem 1997, 272:29390-29397.
• [73]Brazil MI, Chung H, Maxfield FR: Effects of incorporation of immunoglobulin G and complement component C1q on uptake and degradation of Alzheimer's disease amyloid fibrils by microglia. J Biol Chem 2000, 275:16941-16947.
• [74]Chung H, Brazil MI, Irizarry MC, Hyman BT, Maxfield FR: Uptake of fibrillar beta-amyloid by microglia isolated from MSR-A (type I and type II) knockout mice. Neuroreport 2001, 12:1151-1154.
• [75]Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ: Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci 2002, 5:1288-1293.
• [76]Town T, Tan J, Mullan M: CD40 signaling and Alzheimer's disease pathogenesis. Neurochem Int 2001, 39:371-380.
• [77]Tan J, Town T, Mullan M: CD40-CD40L interaction in Alzheimer's disease. Curr Opin Pharmacol 2002, 2:445-451.
• [78]Togo T, Akiyama H, Kondo H, Ikeda K, Kato M, Iseki E, Kosaka K: Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases. Brain Res 2000, 885:117-121.
• [79]Calingasan NY, Erdely HA, Altar CA: Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol Aging 2002, 23:31-39.
• [80]Townsend KP, Town T, Mori T, Lue LF, Shytle D, Sanberg PR, Morgan D, Fernandez F, Flavell RA, Tan J: CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide. Eur J Immunol 2005, 35:901-910.
• [81]Minghetti L, Ajmone-Cat MA, De Berardinis MA, De Simone R: Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Brain Res Rev 2005, 48:251-256.
• [82]Monsonego A, Imitola J, Zota V, Oida T, Weiner HL: Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells. J Immunol 2003, 171:2216-2224.
• [83]Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, et al.: Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000, 6:916-919.
• [84]Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, et al.: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999, 400:173-177.
• [85]Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, et al.: Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci USA 2003, 100:2023-2028.
• [86]Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, et al.: A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000, 408:979-982.
• [87]Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, et al.: A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 2000, 408:982-985.
• [88]Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M: Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 2002, 298:1379.
• [89]Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO: Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003, 9:448-452.
• [90]Monsonego A, Weiner HL: Immunotherapeutic approaches to Alzheimer's disease. Science 2003, 302:834-838.
• [91]Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N: Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 1998, 188:1359-1368.
• [92]Tait JF, Smith C: Phosphatidylserine receptors: role of CD36 in binding of anionic phospholipid vesicles to monocytic cells. J Biol Chem 1999, 274:3048-3054.
• [93]Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB: CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 2002, 160:101-112.
• [94]Brawand P, Fitzpatrick DR, Greenfield BW, Brasel K, Maliszewski CR, De Smedt T: Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J Immunol 2002, 169:6711-6719.
• [95]Kim WK, Ganea D, Jonakait GM: Inhibition of microglial CD40 expression by pituitary adenylate cyclase-activating polypeptide is mediated by interleukin-10. J Neuroimmunol 2002, 126:16-24.
• [96]Prilliman KR, Lemmens EE, Palioungas G, Wolfe TG, Allison JP, Sharpe AH, Schoenberger SP: Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL. J Immunol 2002, 169:4094-4097.
• [97]Quaranta MG, Tritarelli E, Giordani L, Viora M: HIV-1 Nef induces dendritic cell differentiation: a possible mechanism of uninfected CD4(+) T cell activation. Exp Cell Res 2002, 275:243-254.
• [98]Spisek R, Bretaudeau L, Barbieux I, Meflah K, Gregoire M: Standardized generation of fully mature p70 IL-12 secreting monocyte-derived dendritic cells for clinical use. Cancer Immunol Immunother 2001, 50:417-427.
• [99]Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L: TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 2001, 7:612-618.