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Microglia: Features of Polarization and Aging

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Inflammation, Aging, and Oxidative Stress

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Abstract

As a primary immune-like cell of the CNS, the association of microglia with brain injury and neurodegenerative disease has lead to a predominance of opinion as to the negative nature of microglia and their associated inflammatory-related responses. However, how to define what represents an adverse function of these cells continues to remain elusive especially with increasing data demonstrating the very complex nature of these cells and their performance within the CNS. Much of the work examining microglia with aging has been focused on the association of microglia and inflammatory factors as they occur within neurodegenerative conditions. The current chapter is focused rather on our current knowledge regarding the nature of microglia within the aged brain under non-injury or non-disease conditions. Gaining an appreciation of the normal shifts in function and inflammatory states of microglia will contribute to the understanding of how these cells contribute to the onset or progression of neurodegenerative diseases.

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References

  1. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma'ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13:1118–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cajal RY. Contribucion al conocimiento de la meuroglia del cerebro humano. Trab Lab Invest Biol. 1913;11:254.

    Google Scholar 

  3. del Rio Hortega P. Microglia. In: Penfield W, editor. Cytology and cellular pathology of the nervous system. New York: Hoeber; 1932. p. 481–558.

    Google Scholar 

  4. Alliot F, Godin I, Pessac B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Br Res. 1999;117(2):145–52.

    Article  CAS  Google Scholar 

  5. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, ConwaySJ NLG, Stanley ER, Samokhvalov IM, Merad M. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330:841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336(6077):86–90.

    Article  CAS  PubMed  Google Scholar 

  7. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Hölscher C, Müller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci. 2013;16(3):273–80.

    Article  CAS  PubMed  Google Scholar 

  8. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518(7540):547–51.

    Article  PubMed  CAS  Google Scholar 

  9. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19(8):312–8.

    Article  CAS  PubMed  Google Scholar 

  10. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151–70.

    Article  CAS  PubMed  Google Scholar 

  11. Mittelbronn M, Dietz K, Schluesener JH, 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;101:249–55.

    CAS  PubMed  Google Scholar 

  12. Harry GJ, Kraft AD. Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology. 2012;33(2):191–206.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix C. CNS immune privilege: hiding in plain sight. Immunol Rev. 2006;213:48–65.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Schmid CD, Melchior B, Masek K, Puntambekar SS, Danielson PE, Lo DD, Sutcliffe JG, Carson MJ. Differential gene expression in LPS/IFNgamma activated microglia and macrophages: in vitro versus in vivo. J Neurochem. 2009;109 Suppl 1:117–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8(6):752–8.

    Article  CAS  PubMed  Google Scholar 

  16. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.

    Article  CAS  PubMed  Google Scholar 

  17. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10(11):1387–94.

    Article  CAS  PubMed  Google Scholar 

  18. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45.

    Article  CAS  PubMed  Google Scholar 

  19. Mallat M, Marin-Teva JL, Cheret C. Phagocytosis in the developing CNS: more than clearing the corpses. Curr Opin Neurobiol. 2005;15:101–7.

    Article  CAS  PubMed  Google Scholar 

  20. Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J. Microglia and neuronal cell death. Neuron Glia Biol. 2011;7(1):25–40.

    Article  PubMed  Google Scholar 

  21. Dalmau I, Vela JM, Gonzalez B, Finsen B, Castellano B. Dunamics of microglia in the developing rat brain. J Comp Neurol. 2003;458:144–57.

    Article  PubMed  Google Scholar 

  22. Peri F, Nusslein-Volhard C. Live images of neuronal degradation by microglia reveals a role for v0-ATPase al in phagocomal fusion in vivo. Cell. 2008;133:916–27.

    Article  CAS  PubMed  Google Scholar 

  23. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29:3974–80.

    Article  CAS  PubMed  Google Scholar 

  24. Nagamoto-Combs K, Morecraft RJ, Darling WG, Combs CK. Long-term gliosis and molecular changes in the cervical spinal cord of the rhesus monkey after traumatic brain injury. J Neurotrauma. 2010;27(3):565–85.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7:483–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Bumas L, Ragozzino D, Gross CT. Suynaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8.

    Article  CAS  PubMed  Google Scholar 

  27. Olah M, Biber K, Vinet J, Boddeke HW. Microglia phenotype diversity. CNS Neurol Disord Drug Targets. 2011;10(1):108–18.

    Article  CAS  PubMed  Google Scholar 

  28. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikura J, Ishii M, Yamashita T. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci. 2013;16:543–51.

    Article  CAS  PubMed  Google Scholar 

  29. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007;10(12):1538–43.

    Article  CAS  PubMed  Google Scholar 

  30. Goldmann T, Wieghofer P, Müller PF, Wolf Y, Varol D, Yona S, Brendecke SM, Kierdorf K, Staszewski O, Datta M, Luedde T, Heikenwalder M, Jung S, Prinz M. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci. 2013;16(11):1618–26.

    Article  CAS  PubMed  Google Scholar 

  31. Sieweke MH, Allen JE. Beyond stem cells: self-renewal of differentiated macrophages. Science. 2013;342(6161):1242974.

    Article  PubMed  CAS  Google Scholar 

  32. Vallieres L, Sawchenko PE. Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci. 2003;23(12):5197–207.

    CAS  PubMed  Google Scholar 

  33. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Brück W, Priller J, Prinz M. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007;10(12):1544–53.

    Article  CAS  PubMed  Google Scholar 

  34. Mildner A, Mack M, Schmidt H, Brück W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M. CCR2+ Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain. 2009;132:2487–500.

    Article  PubMed  Google Scholar 

  35. King IL, Dickendesher TL, Segal BM. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood. 2009;113(14):3190–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Blau CW, Cowley TR, O’Sullivan J, Grehan B, Browne TC, Kelly L, Birch A, Murphy N, Kelly AM, Kerskens CM, Lynch MA. The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability. Neurobiol Aging. 2012;33:1005. doi:10.1016/jneurobiolaging.2011.09.035.

    Article  PubMed  CAS  Google Scholar 

  37. Enciu AM, Gherghiceanu M, Popescu BO. Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Oxidative Med Cell Longevity 2013:297512. doi:10.1155/2013/297512.

    Google Scholar 

  38. Marques F, Sousa JC, Sousa N, Palha JA. Blood-brain barrier in aging and in Alzheimer’s disease. Mol Neurodeg. 2013;8:38. doi:10.1186/1750-1326-8-38.

    Article  CAS  Google Scholar 

  39. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14(6):392–404.

    Article  CAS  PubMed  Google Scholar 

  40. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16(12):1896–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O'Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, Maniatis T. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4:385–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL. Identification of a unique TGF-beta- dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17(1):131–43.

    Article  CAS  PubMed  Google Scholar 

  43. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shechter R, Schwartz M. CNS sterile injury: just another wound healing? Trends Mol Med. 2013;19(3):135–43.

    Article  PubMed  Google Scholar 

  45. McPherson CA, Merrick BA, Harry GJ. In vivo molecular markers for pro- inflammatory cytokine M1 stage and resident microglia in trimethyltin-induced hippocampal injury. Neurotoxicity Res. 2014;25(1):45–56.

    Article  CAS  Google Scholar 

  46. Mosser DM, Edwards JP. Exploring the spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889–96.

    Article  CAS  PubMed  Google Scholar 

  48. Chinetti-Gbaguidi G, Staels B. Macrophage polarization in metabolic disorders: functions and regulation. Curr Opin Lipidol. 2011;22(5):365–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropath Appl Neurobiol. 2013;39(1):3–18.

    Article  CAS  Google Scholar 

  50. Colton CA. Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimm Pharmacol. 2009;4(4):399–418.

    Article  Google Scholar 

  51. Martinez FO, Gordon S. (2014). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13. doi:10.12703/P6-13.

    Google Scholar 

  52. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177(10):7303–11.

    Article  CAS  PubMed  Google Scholar 

  53. Hu X, Ivashkiv LB. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity. 2009;31:539–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Waddell SJ, Popper SJ, Rubins KH, Griffiths MJ, Brown PO, Levin M, Relman DA. Dissecting interferon-induced transcriptional progrrams in human peripheral blood cells. PLoS One. 2010; doi: http://dx.doi.org/10.1371/journal.pone.0009753.

    Google Scholar 

  55. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.

    Article  CAS  PubMed  Google Scholar 

  57. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604.

    Article  CAS  PubMed  Google Scholar 

  58. Ortega-Gomez A, Perretti M, Soehnlein O. Resolution of inflammation: an integrated review. EMBO Mol Med. 2013;5(5):661–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cherry JD, Olschowka JA, O'Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:98–9. doi:10.1186/1742-2094-11-98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Longbrake EE, Lai W, Ankeny DP, Popovich PG. Characterization and modeling of monocyte-derived macrophages after spinal cord injury. J Neurochem. 2007;102(4):1083–94.

    Article  CAS  PubMed  Google Scholar 

  61. Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. J Leukocyte Biol. 2013;93(6):875–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, Nerlov C. A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci U S A. 2009;106(41):17475–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J, Kim KW, Klein E, Kalchenko V, Bendel P, Lira SA, Jung S, Schwartz M. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity. 2013;38(3):555–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exper Med. 1992;176(1):287–92.

    Article  CAS  Google Scholar 

  65. Henkel JS, Beers DR, Zhao W, Appel SH. Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol. 2009;4(4):389–98.

    Article  PubMed  Google Scholar 

  66. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11(11):750–61.

    Article  CAS  PubMed  Google Scholar 

  67. Mills CD. M1 and M2 macrophages: oracles of health and disease. Critical Rev Immunol. 2012;32(6):463–88.

    Article  CAS  Google Scholar 

  68. Rutschman R, Lang R, Hesse M, Ihle JN, Wynn TA, Murray PJ. Cutting edge: Stat6- dependent substrate depletion regulates nitric oxide production. J Immunol. 2001;166(4):2173–7.

    Article  CAS  PubMed  Google Scholar 

  69. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exper Med. 1993;178(2):605–13.

    Article  CAS  Google Scholar 

  71. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–61.

    Article  CAS  PubMed  Google Scholar 

  72. Morris T, Stables M, Hobbs A, de Souza P, Colville-Nash P, Warner T, Newson J, Bellingan G, Gilroy DW. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol. 2009;183(3):2089–96.

    Article  CAS  PubMed  Google Scholar 

  73. Lisi L, Stigliano E, Lauriola L, Navarra P, Dello RC. Proinflammatory-activated glioma cells induce a switch in microglial polarization and activation status, from a predominant M2b phenotype to a mixture of M1 and M2a/B polarized cells. ASN Neuro. 2014;6(3):171–83.

    Article  PubMed  CAS  Google Scholar 

  74. Fenn AM, Henry CJ, Huang Y, Dugan A, Godbout JP. Lipopolysaccharide- induced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav Immun. 2012;26(5):766–77.

    Article  CAS  PubMed  Google Scholar 

  75. Liu HC, Zheng MH, Du YL, Wang L, Kuang F, Qin HY, Zhang BF, Han H. N9 microglial cells polarized by LPS and IL4 show differential responses to secondary environmental stimuli. Cellular Immunol. 2012;278(1–2):84–90.

    Article  CAS  Google Scholar 

  76. Chhor V, Le Charpentier T, Lebon S, Oré MV, Celador IL, Josserand J, Degos V, Jacotot E, Hagberg H, Sävman K, Mallard C, Gressens P, Fleiss B. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Beh Immun. 2013;32:70–85.

    Article  CAS  Google Scholar 

  77. Freilich RW, Woodbury ME, Ikezu T. Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia. PLoS One. 2013;8(11), e79416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P. Characterization of t he microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J Immunol. 2009;210(1–2):3–12.

    CAS  Google Scholar 

  79. El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol. 2008;9(12):1399–406.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Crane MJ, Daley JM, van Houtte O, Brancato SK, Henry Jr WL, Albina JE. The monocyte to macrophage transition in the murine sterile wound. PLoS One. 2014;9(1), e86660. doi:10.1371/journal.pone.0086660.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014;159(6):1327–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Durafourt BA, Moore CS, Zammit DA, Johnson TA, Zaguia F, Guiot MC, Bar-Or A, Antel JP. Comparison of polarization properties of human adult microglia and blood- derived macrophages. Glia. 2012;60(5):717–27.

    Article  PubMed  Google Scholar 

  83. Chávez-Galán L, Olleros ML, Vesin D, Garcia I. Much More than M1 and M2 Macrophages, There are also CD169(+) and TCR(+) Macrophages. Front Immunol. 2015;6:263. doi:10.3389/fimmu.2015.00263.

    PubMed  PubMed Central  Google Scholar 

  84. Dey A, Allen J, Hankey-Giblin PA. Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages. Front Immunol. 2015;5:683. doi:10.3389/fimmu.2014.00683.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. De Simone R, Vissicchio F, Mingarelli C, De Nuccio C, Visentin S, Ajmone-Cat MA, Minghetti L. Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta. 2013;1832(5):650–9.

    Article  PubMed  CAS  Google Scholar 

  86. Vogel DY, Vereyken EJ, Glim JE, Heijnen PD, Moeton M, van der Valk P, Amor S, Teunissen CE, van Horssen J, Dijkstra CD. Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflammation. 2013;10:35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kan MJ, Lee JE, Wilson JG, Everhart AL, Brown CM, Hoofnagle AN, Jansen M, Vitek MP, Gunn MD, Colton CA. Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease. J Neurosci. 2015;35(15):5969–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40(2):274–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cherry JD, Olschowka JA, O'Banion MK. Are “resting” microglia more “m2”? Front Immunol. 2014;5:594. doi:10.3389/fimmu.2014.00594.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Cell Metab. 2012;15:432–7.

    Article  CAS  PubMed  Google Scholar 

  92. Rodríguez-Prados JC, Través PG, Cuenca J, Rico D, Aragonés J, Martín-Sanz P, Cascante M, Boscá L. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010;185(1):605–14.

    Article  PubMed  CAS  Google Scholar 

  93. Galvan-Peña S, O'Neill LA. Metabolic reprograming in macrophage polarization. Front Immunol. 2014;5:420.

    PubMed  PubMed Central  Google Scholar 

  94. Voloboueva LA, Emery JF, Sun X, Giffard RG. Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose- regulated protein 75/mortalin. FEBS Lett. 2013;587(6):756–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gimeno-Bayon J, Lopez-Lopez A, Rodriguez MJ, Mahy N. Glucose pathways adaptation supports acquisition of activated microglia phenotype. J Neurosci. 2014;92(6):723–31.

    CAS  Google Scholar 

  96. Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 2016;173(4):649–65. doi:10.1111/bph.13139.

    Article  CAS  PubMed  Google Scholar 

  97. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011;472(7344):476–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kletzien RF, Harris PK, Foellmi LA. Glucose-6-phosphate dehydrogenase: a “housekeeping” enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB J. 1994;8(2):174–81.

    CAS  PubMed  Google Scholar 

  99. Salvemini F, Franze A, Iervolino A, Filosa S, Salzano S, Ursini MV. Enhanced glutathione levels and oxido resistance mediated by increased glucose-6-phosphate dehydrogenase expression. J Biol Chem. 1999;274(5):2750–7.

    Article  CAS  PubMed  Google Scholar 

  100. Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990;87(2):682–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994;298(Pt 2):249–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neurosci. 2007;10(11):1387–94.

    Article  CAS  PubMed  Google Scholar 

  103. Varnum MM, Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain. Arch Immunol Therap Exper. 2012;60(4):251–66.

    Article  CAS  Google Scholar 

  104. Colton C, Wilcock DM. Assessing activation states in microglia. CNS Neurol Dis Drug Targets. 2010;9(2):174–91.

    Article  CAS  Google Scholar 

  105. Bordt EA, Polster BM. NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair? Free Radical Biol Med. 2014;76:34–46.

    Article  CAS  Google Scholar 

  106. de Rivero Vaccari JC, Brand 3rd FJ, Berti AF, Alonso OF, Bullock MR, de Rivero Vaccari JP. Mincle signaling in the innate immune response after traumatic brain injury. J Neurotrauma. 2015;32(4):228–36.

    Article  PubMed  Google Scholar 

  107. Labbe K, Saleh M. Cell death in the host response to infection. Cell Death Differ. 2008;15(9):1339–49.

    Article  CAS  PubMed  Google Scholar 

  108. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A. Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology. J Cell Mol Med. 2008;12(6a):2255–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Ann Rev Immunol. 2009;27:229–65.

    Article  CAS  Google Scholar 

  110. Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA, Joosten LA. Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol. 2015;33:49–77.

    Article  CAS  PubMed  Google Scholar 

  111. Shi F, Yang L, Kouadir M, Yang Y, Wang J, Zhou X, Yin X, Zhao D. The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J Neuroinflammation. 2012;9:73. doi:10.1186/1742-2094-9-73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Frank M, Barrientos R, Biedenkapp J, Rudy J, Watkins L, Maier S. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging. 2006;27(5):717–22.

    Article  CAS  PubMed  Google Scholar 

  113. Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci. 2014;15(2):84–97.

    Article  CAS  PubMed  Google Scholar 

  114. Cao L, Fei L, Chang TT, DeLeo JA. Induction of interleukin-1beta by interleukin- 4 in lipopolysaccharide-treated mixed glial cultures: microglial-dependent effects. J Neurochem. 2007;102(2):408–19.

    Article  CAS  PubMed  Google Scholar 

  115. Ferger AI, Campanelli L, Reimer V, Muth KN, Merdian I, Ludolph AC, Witting A. Effects of mitochondrial dysfunction on the immunological properties of microglia. J Neuroinflammation. 2010;7:45. doi:10.1186/1742-2094-7-45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Perry VH, Matyszak MK, Fearn S. Altered antigen expression of microglia in theaged rodent CNS. Glia. 1993;7:60–7.

    Article  CAS  PubMed  Google Scholar 

  117. Sheffield L, Berman N. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging. 1998;19(1):47–55.

    Article  CAS  PubMed  Google Scholar 

  118. Flanary BE, Sammons NW, Nguyen C, Walker D, Streit WJ. Evidence that aging and amyloid promote microglial cell senescence. Rejuvenat Res. 2007;10(1):61–74.

    Article  CAS  Google Scholar 

  119. Lopes KO, Sparks DL, Streit WJ. Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity. Glia. 2008;56(10):1048–60.

    Article  PubMed  Google Scholar 

  120. Luo XG, Ding JQ, Chen SD. Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodeg. 2010;5:12. doi:10.1186/1750-1326-5-12.

    Article  Google Scholar 

  121. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affec chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161–7.

    Article  CAS  PubMed  Google Scholar 

  122. Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset alzheimer disease. Nat Rev Neurol. 2013;9(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  123. Erny D, de Angelis AL H, Jaitin D, Wieghofer P, Staszewski O, David E, Keren- Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermöhlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M. Host microbiota constantly control maturation and function in the CNS. Nat Neurosci. 2015;18:965–77.

    Article  CAS  PubMed  Google Scholar 

  124. Floden AM, Combs CK. Microglia demonstrate age-dependent interaction with amyloid-β fibrils. J Alzheimers Dis. 2011;25(2):279.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Harry GJ, Lefebvre d'Hellencourt C, Bruccoleri A, Schmechel D. Age-dependent cytokine responses: trimethyltin hippocampal injury in wild-type, APOE knockout, and APOE4 mice. Brain Behav Immun. 2000;14(4):288–304.

    Article  CAS  PubMed  Google Scholar 

  126. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11(2):111–28.

    PubMed  PubMed Central  Google Scholar 

  127. Lee EB. Obesity, leptin, and Alzheimer’s disease. Ann N Y Acad Sci. 2011;1243(1):15–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Puig KL, Floden AM, Adhikari R, Golovko MY, Combs CK. Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS One. 2012;7(1), e30378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Buckman LB, Hasty AH, Flaherty DK, Buckman CT, Thompson MM, Matlock BK, Weller K, Ellacot KL. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun. 2013;35:33–42.

    Article  PubMed  CAS  Google Scholar 

  130. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti- inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128(1):92–105.

    Article  CAS  PubMed  Google Scholar 

  131. Perry VH. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol. 2010;120(3):277–86.

    Article  CAS  PubMed  Google Scholar 

  132. Nakanishi H, Wu Z. Microglia-aging: roles of microglial lysosome- and mitochondria- derived reactive oxygen species in brain aging. Behav Brain Res. 2009;201(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  133. Von Bernhardi R, Tichauer JE, Eugenı’ NJ. Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem. 2010;112(5):1099–114.

    Article  CAS  Google Scholar 

  134. Flanary BE, Streit WJ. Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia. J Neurosci Res. 2005;82(2):160–71.

    Article  CAS  PubMed  Google Scholar 

  135. Streit WJ. Microglia and Alzheimer's disease pathogenesis. J Neurosci Res. 2004;77(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  136. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing- associated disorders. Nature. 2011;479(7372):232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Streit WJ, Miller KR, Lopes KO, Njie E. Microglial degeneration in the aging brain—bad news for neurons? Front Biosci. 2008;13:3423–38.

    Article  CAS  PubMed  Google Scholar 

  138. Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neurosci. 1992;48(2):405–15.

    Article  CAS  Google Scholar 

  139. Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD. Turnover of resident retinal microglia in the normal adult mouse. Glia. 2007;55(11):1189–98.

    Article  PubMed  Google Scholar 

  140. Hua K, Schindler MK, Mcquail JA, Forbes ME, Riddle DR. Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats. PLoS One. 2012;7(12), e52728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Conde JR, Streit WJ. Microglia in the aging brain. J Neuropath Exp Neurol. 2006;65:199–203.

    Article  PubMed  Google Scholar 

  142. Long JM, Kalehua AN, Muth NJ, Calhoun ME, Jucker M, Hengemihle JM, Ingram DK, Mouton PR. Stereological analysis of astrocyte and microglia in aging mouse hippocampus. Neurobiol Aging. 1998;19(5):497–503.

    Article  CAS  PubMed  Google Scholar 

  143. Vaughan DW, Peters A. Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J Neurocytol. 1974;3(4):405–29.

    Article  CAS  PubMed  Google Scholar 

  144. Tremblay ME, Zettel ML, Ison JR, Allen PD, Majewska AK. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia. 2012;60(4):541–58.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT. Age-related alterations in the dynamic behavior of microglia. Aging Cell. 2011;10(2):263–76.

    Article  CAS  PubMed  Google Scholar 

  146. Hefendehl JK, Neher JJ, Suhs RB, Kohsaka S, Skodras A, Jucker M. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell. 2014;13(1):60–9.

    Article  CAS  PubMed  Google Scholar 

  147. Streit WJ, Xue Q-S. The Brain’s aging immune system. Aging Dis. 2010;1(3):254–61.

    PubMed  PubMed Central  Google Scholar 

  148. Hart AD, Wyttenbach A, Perry VH, Teeling JL. Age related changes in microglial phenotype vary between CNS regions: Grey versus white matter differences. Brain Behav Immun. 2012;26(5):754–65.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Maeda K, Nakai M, Maeda S, Kawamata T, Yamaguchi T, Tanaka C. Possible different mechanism between amyloid-beta (25-35)-and substance P-induced chemotaxis of murine microglia. Gerontology. 1997;43(Suppl1):11–5.

    CAS  PubMed  Google Scholar 

  150. Ard MD, Cole GM, Wei J, Mehrle AP, Fratkin JD. Scavenging of Alzheimer’s amyloid beta-protein by microglia in culture. J Neurosci Res. 1996;43(2):190–202.

    Article  CAS  PubMed  Google Scholar 

  151. Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of amyloid-(plaques in a mouse model of Alzheimer’s disease. Nature. 2008;451(7179):720–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Koenigsknecht-Talboo J, Meyer-Luehmann M, Parsadanian M, Garcia-Alloza M, Finn MB, Hyman BT, Bacskai BJ, Holtzman DM. Rapid microglial response around amyloid pathology after systemic antibody administration in PDAPP mice. J Neurosci. 2008;28(52):14156–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science. 2013;339(6116):156–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013;77(1):10–8.

    Article  CAS  PubMed  Google Scholar 

  155. Siskova Z, Tremblay ME. Microglia and synapse: interactions in health and neurodegeneration. Neural Plast. 2013:425845. doi: 10.1155/2013/425845.

    Google Scholar 

  156. Ravichandran KS. “Recruitment signals” from apoptotic cells: invitation to a quiet meal. Cell. 2003;113(7):817–20.

    Article  CAS  PubMed  Google Scholar 

  157. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S. Identification of Tim4 as a phosphatidylserine receptor. Nature. 2007;450(7168):435–9.

    Article  CAS  PubMed  Google Scholar 

  158. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature. 2007;446(7139):1091–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005;201(4):647–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007;4(4), e124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. 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(1-2):92–9.

    Article  CAS  PubMed  Google Scholar 

  162. Wong PM, Puente C, Ganley IG, Jiang X. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy. 2013;9(2):124–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Solito E, Sastre M. Microglia function in Alzheimer’s disease. Front Pharmacol. 2012;3:1–10.

    Article  CAS  Google Scholar 

  164. Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL. Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One. 2013;8(4), e60921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR. Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell. 2007;18(4):1490–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Prokop S, Miller KR, Heppner FL. Microglia actions in Alzheimer’s disease. Acta Neuropathol. 2013;126(4):461–77.

    Article  CAS  PubMed  Google Scholar 

  167. Mandrekar S, Jiang Q, Lee CYD, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE. Microglia mediate the clearance of soluble a through fluid phase macropinocytosis. J Neurosci. 2009;29(13):4252–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Miners JS, Barua N, Kehoe PG, Gill S, Love S. Ab-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol. 2011;70(11):944–59.

    Article  CAS  PubMed  Google Scholar 

  169. Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H. IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia. J Immunol. 2008;181(9):6503–13.

    Article  CAS  PubMed  Google Scholar 

  170. Qiu WQ. Insulin-degrading enzyme regulates extracellular levels of amyloid beta protein by degradation. J Biol Chem. 1998;273(49):32730–8.

    Article  CAS  PubMed  Google Scholar 

  171. Grathwohl SA, Kälin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. 2009;12(11):1361–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia. 2007;55(4):412–24.

    Article  PubMed  Google Scholar 

  173. Henry CJ, Huang Y, Wynne AM, Godbout JP. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines. Brain Behav Immun. 2009;23(3):309–17.

    Article  CAS  PubMed  Google Scholar 

  174. Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI, Loane DJ. Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging. 2013;34(5):1397–411.

    Article  CAS  PubMed  Google Scholar 

  175. Sheng JG, Mrak RE, Griffin WS. Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol. 1998;95(3):229–34.

    Article  CAS  PubMed  Google Scholar 

  176. Strohmeyer R, Ramirez M, Cole GJ, Mueller K, Rogers J. Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer’s disease brain. J Neuroimmunol. 2002;131(1–2):135–46.

    Article  CAS  PubMed  Google Scholar 

  177. Schindler M, Forbes M, Robbins M, Riddle D. Aging-dependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys. 2008;70(3):826–34.

    Article  PubMed  Google Scholar 

  178. Harry GJ. Microglia during development and aging. Pharmacol Therap. 2013;139(3):313–26.

    Article  CAS  Google Scholar 

  179. Wong AM, Patel NV, Patel NK, Wei M, Morgan TE, de Beer MC, de Villiers WJ, Finch CE. Macrosialin increases during normal brain aging are attenuated by caloric restriction. Neurosci Lett. 2005;390(2):76–80.

    Article  CAS  PubMed  Google Scholar 

  180. Dilger RN, Johnson RW. Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukocyte Biol. 2008;84(4):932–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Sheng JG, Mrak RE, Griffin WS. Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol. 1998;95(3):229–34.

    Article  CAS  PubMed  Google Scholar 

  182. Minogue AM, Jones RS, Kelly RJ, McDonald CL, Connor TJ, Lynch MA. Age- associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice. Neurobiol Aging. 2014;35(6):1442–52.

    Article  CAS  PubMed  Google Scholar 

  183. Lively S, Schlichter LC. Age-related comparisons of evolution of the inflammatory response after intracerebral hemorrhage in rats. Trans Stroke Res. 2012;3(S1):132–46.

    Article  CAS  Google Scholar 

  184. Lee DC, Ruiz CR, Lebson L, Selenica ML, Rizer J, Hunt Jr JB, Rojiani R, Reid P, Kammath S, Nash K, Dickey CA, Gordon M, Morgan D. Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiol Aging. 2013;34(6):1610–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Ye SM, Johnson RW. Increased interleukin-6 expression by microglia from brain of aged mice. J Immunol. 1999;93(1–2):139–48.

    CAS  Google Scholar 

  186. Yu WH, Go L, Guinn BA, Fraser PE, Westaway D, McLaurin J. Phenotypic and functional changes in glial cells as a function of age. Neurobiol Aging. 2002;23(1):105–15.

    Article  CAS  PubMed  Google Scholar 

  187. Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging. 2012;33(1):195. doi:10.1016/j.neurobiolaging.2010.05.008.

    Article  PubMed  CAS  Google Scholar 

  188. Lai AY, Dibal CD, Armitage GA, Winship IR, Todd KG. Distinct activation profiles in microglia of different ages: a systematic study in isolated embryonic to aged microglial cultures. Neurosci. 2013;254:185–95.

    Article  CAS  Google Scholar 

  189. Wynne AM, Henry CJ, Huang Y, Cleland A, Godbout JP. Protracted down-regulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav Immun. 2010;24(7):1190–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, Hudson CE, Cole MJ, Harrison JK, Bickford PC, Gemma C. Fractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats. NBA. 2011;32(11):2030–44.

    CAS  Google Scholar 

  191. Cox FF, Carney D, Miller A-M, Lynch MA. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav Immun. 2012;26(5):789–96.

    Article  CAS  PubMed  Google Scholar 

  192. Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol EM. Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging. 2014;35:1–14.

    Article  CAS  PubMed  Google Scholar 

  193. Ma W, Cojocaru R, Gotoh N, Gieser L, Villasmil R, Cogliati T, Swaroop A, Wong WT. Gene expression changes in aging retinalmicroglia:relationship to microglial support functions and regulation of activation. Neurobiol Aging. 2013;34:2310–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Wes PD, Holtman IR, Boddeke EWGM, Moller T, Eggen BJL. Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. Glia. 2015;64(2):197–213. doi:10.1002/glia.22866.

    Article  PubMed  Google Scholar 

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Acknowledgment

This work was supported by the Division National Toxicology Program, National Institute of Environmental Health Sciences, #1Z01ES101623 and ES021164.

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  1. National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Neurotoxicology Group, 111 T.W. Alexander Drive, MD E1-07, Research Triangle Park, NC, 27709, USA

    G. Jean Harry Ph.D. & Christopher A. McPherson

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Correspondence to G. Jean Harry Ph.D. .

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  1. Department of Medicine, Center for Occupational and Environmental Health, University of California, Irvine, California, USA

    Stephen C. Bondy

  2. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA

    Arezoo Campbell

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Harry, G.J., McPherson, C.A. (2016). Microglia: Features of Polarization and Aging. In: Bondy, S., Campbell, A. (eds) Inflammation, Aging, and Oxidative Stress. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-33486-8_3

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