Skip to main content

Advertisement

SpringerLink
Log in

Microglia in the Physiology and Pathology of Brain

  • Review
  • Published:
Proceedings of the National Academy of Sciences, India Section B: Biological Sciences Aims and scope Submit manuscript

Abstract

Microglia are the immune cells of the brain involved in regulation and maintenance of brain micro-environment. These cells not only play imperative role in shaping the brain neural networks during development but also protect the brain from any disparaging condition throughout the life as first line of combatants. Interestingly, these cells exhibit dual nature in various neuropathological conditions. Depending upon the quantum of brain insult, they acquire different morphology which in favour either suppress the severity or aggravate the situation by releasing several immune-mediated molecules. This review summarizes the properties of microglia in healthy and diseased brain and explains their dual nature in various neuropathological disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Del Rio-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system. Paul B Hoeber, New York, pp 482–534

    Google Scholar 

  2. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pont-Lezica L, Béchade C, Belarif-Cantaut Y, Pascual O, Bessis A (2011) Physiological roles of microglia during development. J Neurochem 119(5):901–908

    Article  CAS  PubMed  Google Scholar 

  4. Nayak D, Roth TL, McGavern DB (2014) Microglia development and function. Annu Rev Immunol 32:367–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45

    Article  PubMed  PubMed Central  Google Scholar 

  7. Neiva I, Malva JO, Valero J (2014) Can we talk about microglia without neurons? A discussion of microglial cell autonomous properties in culture. Front Cell Neurosci 8:202

    Article  PubMed  PubMed Central  Google Scholar 

  8. Prinz M, Mildner A (2011) Microglia in the CNS: immigrants from another world. Glia 59(2):177–187

    Article  PubMed  Google Scholar 

  9. Gomez Perdiguero E, Schulz C, Geissmann F (2013) Development and homeostasis of “resident” myeloid cells: the case of the microglia. Glia 61(1):112–120

    Article  PubMed  Google Scholar 

  10. Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R (2014) Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211(8):1533–1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5):300–312

    Article  CAS  PubMed  Google Scholar 

  12. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318

    Article  CAS  PubMed  Google Scholar 

  13. Hellwig S, Heinrich A, Biber K (2013) The brain’s best friend: microglial neurotoxicity revisited. Front Cell Neurosci 7:71

    Article  PubMed  PubMed Central  Google Scholar 

  14. Niquet J, Ben-Ari Y, Repressa A (1994) Glial reaction after seizure induced hippocampal lesion: immunohistochemical characterization of proliferating glial cells. J Neurocytol 23(10):641–656

    Article  CAS  PubMed  Google Scholar 

  15. Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181(6):3733–3739

    Article  CAS  PubMed  Google Scholar 

  16. Luo XG, Chen SD (2012) The changing phenotype of microglia from homeostasis to disease. Transl Neurodegener 1:9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

    Article  CAS  PubMed  Google Scholar 

  18. Gregory CD, Devitt A (2004) The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically? Immunology 113:1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  20. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev 11(11):775–787

    Article  CAS  Google Scholar 

  21. Boya J, Calvo JL, Carbonell AL, Borregon A (1991) A lectin histochemistry study on the development of rat microglial cells. J Anat 175:229–236

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Monier A, Evrard P, Gressens P et al (2006) Distribution and differentiation of microglia in the human encephalon during the first two trimesters of gestation. J Comp Neurol 499(4):565–582

    Article  CAS  PubMed  Google Scholar 

  24. Rezaie P, Male D (2002) Mesoglia and microglia—a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci 11(4):325–374

    Article  PubMed  Google Scholar 

  25. Alliot F, Lecain E, Grima B, Pessac B (1991) Microglial progenitors with a high proliferative potential in the embryonic and adult mouse brain. Proc Natl Acad Sci USA 88(4):1541–1545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hickey WF, Vass K, Lassmann H (1992) Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol 51(3):246–256

    Article  CAS  PubMed  Google Scholar 

  27. Lassmann H, Hickey WF (1993) Radiation bone marrow chimeras as a tool to study microglia turnover in normal brain and inflammation. Clin Neuropathol 12(5):284–285

    CAS  PubMed  Google Scholar 

  28. Shepard JL, Zon LI (2000) Developmental derivation of embryonic and adult macrophages. Curr Opin Hematol 7(1):3–8

    Article  CAS  PubMed  Google Scholar 

  29. Takahashi K (2001) Development and differentiation of macrophages and related cells: historical review and current concepts. J Clin Exp Hematop 41:1–33

    Article  Google Scholar 

  30. Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292

    Article  CAS  PubMed  Google Scholar 

  31. Yokoyama A, Yang L, Itoh S, Mori K, Tanaka J (2004) Microglia, a potential source of neurons, astrocytes and oligodendrocytes. Glia 45(1):96–104

    Article  PubMed  Google Scholar 

  32. Matsuda S, Niidome T, Nonaka H, Goto Y, Fujimura K, Kato M et al (2008) Microtubule-associated protein 2-positive cells derived from microglia possess properties of functional neurons. Biochem Biophys Res Commun 368(4):971–976

    Article  CAS  PubMed  Google Scholar 

  33. Rakic S, Zecevic N (2000) Programmed cell death in the developing human telencephalon. Eur J Neurosci 12(8):2721–2734

    Article  CAS  PubMed  Google Scholar 

  34. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456–1458

    Article  CAS  PubMed  Google Scholar 

  35. Schafer DP, Lehrman EK, Stevens B (2013) The ‘‘Quad-Partite’’ synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61(1):24–36

    Article  PubMed  Google Scholar 

  36. Farinas I, Cano-Jaimez M, Bellmunt E, Soriano M (2002) Regulation of neurogenesis by neurotrophins in developing spinal sensory ganglia. Brain Res Bull 57(6):809–816

    Article  CAS  PubMed  Google Scholar 

  37. Miller FD, Kaplan DR (2001) Neurotrophin signalling pathways regulating neuronal apoptosis. Cell Mol Life Sci 58(8):1045–1053

    Article  CAS  PubMed  Google Scholar 

  38. Nakajima K, Honda S, Tohyama Y, Imai Y, Kohsaka S, Kurihara T (2001) Neurotrophin secretion from cultured microglia. J Neurosci Res 65(4):322–331

    Article  CAS  PubMed  Google Scholar 

  39. Bansal R (2002) Fibroblast growth factors and their receptors in oligodendrocyte development: implications for demyelination and remyelination. Dev Neurosci 24(1):35–46

    Article  CAS  PubMed  Google Scholar 

  40. Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J et al (2009) Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57(8):835–849

    Article  PubMed  Google Scholar 

  41. Tremblay MÈ, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29(13):3974–3980

    Article  CAS  PubMed  Google Scholar 

  43. Aloisi F (2001) Immune function of microglia. Glia 36(2):165–179

    Article  CAS  PubMed  Google Scholar 

  44. Ekdahl CT, Kokaia Z, Lindvall O (2009) Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 158(3):1021–1029

    Article  CAS  PubMed  Google Scholar 

  45. Gomes-Leal W (2012) Microglial physiopathology: how to explain the dual role of microglia after acute neural disorders? Brain Behav 2(3):345–356

    Article  PubMed  PubMed Central  Google Scholar 

  46. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596–1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82(2):380–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hughes EG, Bergles DE (2014) Hidden progenitors replace microglia in the adult brain. Neuron 82(2):253–255

    Article  CAS  PubMed  Google Scholar 

  49. Ben Achour S, Pascual O (2010) Glia: the many ways to modulate synaptic plasticity. Neurochem Int 57(4):440–445

    Article  CAS  PubMed  Google Scholar 

  50. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553

    Article  CAS  PubMed  Google Scholar 

  51. Hayashi Y, Ishibashi H, Hashimoto K, Nakanishi H (2006) Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 53(6):660–668

    Article  PubMed  Google Scholar 

  52. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA et al (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 31(45):16241–16250

    Article  CAS  PubMed  Google Scholar 

  53. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K et al (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438(7070):1017–1021

    Article  CAS  PubMed  Google Scholar 

  54. Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci USA 109(4):E197–E205

    Article  CAS  PubMed  Google Scholar 

  55. Tremblay MÈ, Zettel ML, Ison JR, Allen PD, Majewska AK (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60(4):541–558

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yung RL, Julius A (2008) Epigenetics, aging and autoimmunity. Autoimmunity 41(4):329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45(2):208–212

    Article  PubMed  Google Scholar 

  58. Kushwaha S (2009) Age related changes in astrocytes and microglia in hippocampus and striate cortex. PhD Thesis, Jiwaji University, Gwalior, India, p 93

  59. Streit WJ (2006) Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 29(9):506–510

    Article  CAS  PubMed  Google Scholar 

  60. Godbout JP, Johnson RW (2009) Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin North Am 29(2):3213–3237

    Article  Google Scholar 

  61. Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55(4):412–424

    Article  PubMed  Google Scholar 

  62. Wynne AM, Henry CJ, Godbout JP (2009) Immune and behavioral consequences of microglial reactivity in the aged brain. Integr Comp Biol 49(3):254–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dilger RN, Johnson RW (2008) Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 84(4):932–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW (2008) Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 22(3):301–311

    Article  CAS  PubMed  Google Scholar 

  65. Mutnal MB, Hu S, Little MR, Lokensgard JR (2011) Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-γ. J Neurovirol 17(5):424–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Patro IK, Pathak S, Patro N (2005) Central responses to peripheral nerve injury: role of non-neuronal cells. In: Thakur MK, Prasad S (eds) Molecular and cellular neurobiology. Narosa publishing house, Delhi, p 217

    Google Scholar 

  67. Patro IK, Nagayach A, Patro N (2010) Iba1 expressing microglia in the dorsal root ganglia become activated following peripheral nerve injury in rats. Indian J Exp Biol 48(2):110–116

    PubMed  Google Scholar 

  68. Patro N, Patro IK (2004) Effect of immunactivator (poly I:C) on the rat cerebral cortex. J Tissue Res 4(1):71–74

    Google Scholar 

  69. Patro IK, Amit Shrivastava M, Bhumika S, Patro N (2010) Poly I: C induced microglial activation impairs motor activity in adult rats. Indian J Exp Biol 48:104–109

    CAS  PubMed  Google Scholar 

  70. Davies CA, Loddick SA, Stroemer RP, Hunt J, Rothwell NJ (1998) An integrated analysis of the progression of cell responses induced by permanent focal middle cerebral artery occlusion in the rat. Exp Neurol 154(1):199–212

    Article  CAS  PubMed  Google Scholar 

  71. Nagayach A, Patro N, Patro I (2014) Experimentally induced diabetes causes glial activation, glutamate toxicity and cellular damage leading to changes in motor function. Front Cell Neurosci 8:355. doi:10.3389/fncel.2014.00355

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Nagayach A, Patro N, Patro I (2014) Astrocytic and microglial response in experimentally induced diabetic rat brain. Metab Brain Dis 29(3):747–761

    Article  CAS  PubMed  Google Scholar 

  73. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155

    Article  PubMed  Google Scholar 

  74. Suzumura A (2002) Microglia: immunoregulatory cells in the central nervous system. Nagoya J Med Sci 65(1–2):9–20

    CAS  PubMed  Google Scholar 

  75. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  CAS  PubMed  Google Scholar 

  76. Rivest S (2003) Molecular insights on the cerebral innate immune system. Brain Behav Immun 17(1):13–19

    Article  CAS  PubMed  Google Scholar 

  77. Sondag CM, Dhawan G, Combs CK (2009) Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflammation 6:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Chao CC, Hu S, Gekker G, Novick WJ Jr, Remington JS, Peterson PK (1993) Effects of cytokines on multiplication of Toxoplasma gondii in microglial cells. J Immunol 150(8 Pt 1):3404–3410

    CAS  PubMed  Google Scholar 

  79. Möller T, Weinstein JR, Hanisch UK (2006) Activation of microglial cells by thrombin: past, present and future. Semin Thromb Hemost 32(Suppl 1):69–76

    Article  PubMed  CAS  Google Scholar 

  80. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766

    CAS  PubMed  Google Scholar 

  81. Itagaki S, Mcgeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24(3):173–182

    Article  CAS  PubMed  Google Scholar 

  82. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12(9):1005–1015

    CAS  PubMed  Google Scholar 

  83. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sheng JG, Mrak RE, Griffin WS (1997) Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alphamicroglia and S100beta-astrocytes with neurofibrillary tangle stages. J Neuropathol Exp Neurol 56:285–290

    Article  CAS  PubMed  Google Scholar 

  85. Cras P, Kawai M, Lowery D, Gonzalez-DeWhitt P, Greenberg B, Perry G (1991) Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc Natl Acad Sci USA 88:7552–7556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li Y, Liu L, Barger SW, Griffin WS (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 23(5):1605–1611

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3):337–351

    Article  CAS  PubMed  Google Scholar 

  88. Streit W, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485

    Article  PubMed  PubMed Central  Google Scholar 

  89. Krause DL, Müller N (2010) Neuroinflammation, microglia and implications for anti–Inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis. doi:10.4061/2010/732806

    PubMed  PubMed Central  Google Scholar 

  90. Mizuno T (2012) The biphasic role of microglia in Alzheimer’s disease. Int J Alzheimer’s Dis, Article ID 737846, 9 p

  91. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19(6):533–542

    Article  CAS  PubMed  Google Scholar 

  92. Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106(6):518–526

    Article  CAS  PubMed  Google Scholar 

  93. Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann NY Acad Sci 991:214–218

    Article  CAS  PubMed  Google Scholar 

  94. Standaert DG, Theodore S, Cao SW, McLean P (2009) α-Synuclein triggers microglial activation and adaptive immunity in a mouse model of Parkinson disease. Neurology 72:A438

    Google Scholar 

  95. Tambuyzer BR, Ponsaerts P, Nouwen EJ (2009) Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol 85(3):352–370

    Article  CAS  PubMed  Google Scholar 

  96. Peterson LJ, Flood PM (2012) Oxidative stress and microglial cells in Parkinson’s disease. Mediat Inflamm 2012:401264. doi:10.1155/2012/401264

    Article  CAS  Google Scholar 

  97. Polazzi E, Altamira LEP, Eleuteri S, Barbaro R, Casadio C, Contestabile A, Monti B (2009) Neuroprotection of microglial conditioned medium on 6-hydroxydopamine-induced neuronal death: role of transforming growth factor β-2. J Neurochem 110(2):545–556

    Article  CAS  PubMed  Google Scholar 

  98. Ramsey CP, Tansey MG (2014) A survey from 2012 of evidence for the role of neuroinflammation in neurotoxin animal models of Parkinson’s disease and potential molecular targets. Exp Neurol 256:126–132

    Article  CAS  PubMed  Google Scholar 

  99. Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517

    Article  CAS  PubMed  Google Scholar 

  100. Giunti D, Parodi B, Cordano C, Uccelli A, Kerlero de Rosbo N (2014) Can we switch microglia’s phenotype to foster neuroprotection? Focus multiple sclerosis. Immunology 141(3):328–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jiang Z, Jiang JX, Zhang GX (2014) Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett 160(1):17–22

    Article  CAS  PubMed  Google Scholar 

  102. Prinz M, Tay TL, Wolf Y, Jung S (2014) Microglia: unique and common features with other tissue macrophages. Acta Neuropathol. doi:10.1007/s00401-014-1267-1

    Google Scholar 

  103. Chastain EM, Duncan DS, Rodgers JM, Miller SD (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812:265–274

    Article  CAS  PubMed  Google Scholar 

  104. Bhasin M, Wu M, Tsirka SE (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol 8:10

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, Schwartz A, Smirnov I, Pollack A, Jung S, Schwartz M (2006) Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Investig 116(4):905–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16(9):1211–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Merson TD, Binder MD, Kilpatrick TJ (2010) Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. NeuroMol Med 12(2):99–132

    Article  CAS  Google Scholar 

  108. Napoli I, Neumann H (2009) Microglial clearance function in health and disease. Neuroscience 158(3):1030–1038

    Article  CAS  PubMed  Google Scholar 

  109. van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ, Witte ME, Geurts JJ, de Vries HE, Peferoen-Baert R, van den Elsen PJ, van der Valk P, Amor S (2012) Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflamm 9:156

    Google Scholar 

  110. Appel SH, Zhao W, Beers DR, Henkel JS (2011) The Microglial-motoneuron dialogue in ALS. Acta Myol 30(1):4–8

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392

    Article  PubMed  CAS  Google Scholar 

  112. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ et al (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an (11C) (R)-PK11195 positron emission tomography study. Neurobiol Dis 15(3):601–609

    Article  CAS  PubMed  Google Scholar 

  113. Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256

    Article  CAS  PubMed  Google Scholar 

  114. Dewil M, Van Den Bosch L, Robberecht W (2007) Microglia in amyotrophic lateral sclerosis. Acta Neurol Belg 107(3):63–70

    PubMed  Google Scholar 

  115. Chiu IM, Chen A, Zheng Y et al (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci USA 105:17913–17918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R (2003) Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 183(1):25–33

    Article  PubMed  Google Scholar 

  117. Weinstein JR, Koerner IP, Möller T (2011) Microglia in ischemic brain injury. Future Neurol 5(2):227–246

    Article  Google Scholar 

  118. Lai AY, Todd KG (2006) Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines. Glia 53(8):809–816

    Article  PubMed  Google Scholar 

  119. Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43(4):348–364

    Article  CAS  PubMed  Google Scholar 

  120. Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, Dinkel K (2006) Microglia provide neuroprotection after ischemia. FASEB J 20(6):714–716

    CAS  PubMed  Google Scholar 

  121. Denes A, Vidyasagar R, Feng J et al (2007) Proliferating resident microglia after focal cerebral ischemia in mice. J Cereb Blood Flow Metab 27(12):1941–1953

    Article  CAS  PubMed  Google Scholar 

  122. Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19(5):1708–1716

    CAS  PubMed  Google Scholar 

  123. Hsiao Y, Chern Y (2009) Targeting glial cells to elucidate the pathogenesis of Huntington’s disease. Mol Neurobiol 41(2–3):248–255

    Google Scholar 

  124. Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA et al (2006) Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology 66(11):1638–1643

    Article  CAS  PubMed  Google Scholar 

  125. Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, Cattaneo E et al (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 17(4):513–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Giorgini F, Moller T, Kwan W, Zwilling D, Wacker JL, Hong S et al (2008) Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J Biol Chem 283(12):7390–7400

    Article  CAS  PubMed  Google Scholar 

  127. Kwan W, Träger U, Davalos D, Chou A, Bouchard J, Andre R et al (2012) Mutant huntingtin impairs immune cell migration in Huntington disease. J Clin Invest 122(12):4737–4747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E et al (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 205(8):1869–1877

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Milnerwood AJ, Raymond LA (2010) Early synaptic pathophysiology in neurodegeneration: insights from Huntington’s disease. Trends Neurosci 33(11):513–523

    Article  CAS  PubMed  Google Scholar 

  130. Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitoxicity. Brain 132(Pt 11):3152–3164

    Article  PubMed  Google Scholar 

  131. Van Everbroeck B, Dewulf E, Pals P, Lübke U, Martin JJ, Cras P (2002) The role of cytokines, astrocytes, microglia and apoptosis in Creutzfeldt-Jakob disease. Neurobiol Aging 23(1):59–64

    Article  PubMed  Google Scholar 

  132. Brown DR, Besinger A, Herms JW, Kretzschmar HA (1998) Microglial expression of the prion protein. Neuroreport 9(7):1425–1429

    Article  CAS  PubMed  Google Scholar 

  133. Brown DR (2001) Microglia and prion disease. Microsc Res Tech 54(2):71–80

    Article  CAS  PubMed  Google Scholar 

  134. Giese A, Brown DR, Groschup MH, Feldmann C, Haist I, Kretzschmar HA (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8(3):449–557

    Article  CAS  PubMed  Google Scholar 

  135. Guiroy DC, Wakayama I, Liberski PP, Gajdusek DC (1994) Relationship of microglia and scrapie amyloid-immunoreactive plaques in kuru, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Acta Neuropathol 87(5):526–530

    Article  CAS  PubMed  Google Scholar 

  136. Peyrin M, Lasmézas CI, Haïk S, Tagliavini F, Salmona M, Williams A et al (1999) Microglial cells respond to amyloidogenic PrP peptide by the production of inflammatory cytokines. Neuroreport 10(4):723–729

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lorger M (2012) Tumor microenvironment in the brain. Cancers 4(1):218–243

    Article  PubMed  PubMed Central  Google Scholar 

  139. Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3:489–501

    Article  CAS  PubMed  Google Scholar 

  140. Guo P, Imanishi Y, Cackowski FC, Jarzynka MJ, Tao HQ, Nishikawa R et al (2005) Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease and laminin 5 gamma 2 correlates with the invasiveness of human glioma. Am J Pathol 166(3):877–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Leung SY, Wong MP, Chung LP, Chan AS, Yuen ST (1997) Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol 93(5):518–527

    Article  CAS  PubMed  Google Scholar 

  142. Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumors. J Neurosci Res 81(3):447–455

    Article  CAS  PubMed  Google Scholar 

  143. Glass R, Synowitz M, Kronenberg G, Walzlein JH, Markovic DS, Wang LP et al (2005) Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 25(10):2637–2646

    Article  CAS  PubMed  Google Scholar 

  144. Schartner JM, Hagar AR, Van Handel M, Zhang L, Nadkarni N, Badie B (2005) Impaired capacity for upregulation of MHC class II in tumour-associated microglia. Glia 51(4):279–285

    Article  PubMed  Google Scholar 

  145. Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumours. Glia 40(2):252–259

    Article  PubMed  Google Scholar 

  146. Sliwa M, Markovic D, Gabrusiewicz K, Synowitz M, Glass R, Zawadzka M et al (2007) The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A. Brain 130(Pt 2):476–489

    Article  PubMed  Google Scholar 

  147. Murata J, Ricciardi-Castagnoli P, Dessousl’eglise Mange P, Martin F, Juillerat-Jeanneret L (1997) Microglial cells induce cytotoxic effects toward colon carcinoma cells: measurement of tumor cytotoxicity with a gamma-glutamyl transpeptidase assay. Int J Cancer 70(2):169–174

    Article  CAS  PubMed  Google Scholar 

  148. Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P (1988) The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 239(4840):586–592

    Article  CAS  PubMed  Google Scholar 

  149. Persidsky Y, Ghorpade A, Rasmussen J, Limoges J, Xj Liu, Stins M et al (1999) Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis. Am J Pathol 155(5):1599–1611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. D’Aversa TG, Eugenin EA, Berman JW (2005) NeuroAIDS: contributions of the human immunodeficiency virus-1 proteins Tat and gp120 as well as CD40 to microglial activation. J Neurosci Res 81(3):436–446

    Article  PubMed  CAS  Google Scholar 

  151. Williams KC, Hickey WF (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu Rev Neuorsci 25:537–562

    Article  CAS  Google Scholar 

  152. Persidsky Y, Gendelman HE (2003) Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection. J Leukoc Biol 74(5):691–701

    Article  CAS  PubMed  Google Scholar 

  153. Tripathi S, Patro I, Mahadevan A, Patro N, Phillip M, Shankar SK (2014) Glial alterations in tuberculous and cryptococcal meningitis and their relation to HIV co-infection—a study on human brains. J Infect Dev Ctries 8(11):1421–1443

    Article  PubMed  Google Scholar 

  154. Marker DF, Puccini JM, Mockus TE, Barbieri J, Lu SM, Gelbard HA (2012) LRRK2 kinase inhibition prevents pathological microglial phagocytosis in response to HIV-1 Tat protein. J Neuroinflammation 9:261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gelbard HA, Dewhurst S, Maggirwar SB, Kiebala M, Polesskaya O, Gendelman HE (2010) Rebuilding synaptic architecture in HIV-1 associated neurocognitive disease: a therapeutic strategy based on modulation of mixed lineage kinase. Neurotherapeutics 7(4):392–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Parthasarathy G, Philipp MT (2012) Review: apoptotic mechanisms in bacterial infections of the central nervous system. Front Immunol 3:306

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ovanesov MV, Moldovan K, Smith K, Vogel MW, Pletnikov MV (2008) Persistent borna disease virus (BDV) infection activates microglia prior to a detectable loss of granule cells in the hippocampus. J Neuroinflammation 5:16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Thongtan T, Thepparit C, Smith DR (2012) The involvement of microglial cells in Japanese encephalitis infections. Clin Dev Immunol 2012:890586

    Article  PubMed  PubMed Central  Google Scholar 

  159. Nau R, Bruck W (2002) Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. Trends Neurosci 25(1):38–45

    Article  CAS  PubMed  Google Scholar 

  160. Deininger MH, Kremsner PG, Meyermann R, Schluesener H (2002) Macrophages/microglial cells in patients with cerebral malaria. Eur Cytokine Netw 13(2):173–185

    CAS  PubMed  Google Scholar 

  161. Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83(5):711–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Block ML, Zecca L, Hong JS (2007) Microglia–mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69

    Article  CAS  PubMed  Google Scholar 

  163. Daulhac L, Maffre V, Mallet C, Etienne M, Privat AM, Kowalski-Chauvel A et al (2011) Phosphorylation of spinal N-methyl D-aspartate receptor NR1 subunits by extracellular signal-regulated kinase in the spinal dorsal horn neurons and microglia contributes to diabetes-induced painful neuropathy. Eur J Pain 15:169.e1–169.e12

    Google Scholar 

  164. Grigsby JG, Cardona SM, Pouw CE, Muniz A, Mendiola AS, Tsin AT et al (2014) The role of microglia in diabetic retinopathy. J Ophthalmol 2014:705783

    PubMed  PubMed Central  Google Scholar 

  165. Wang D, Couture R, Hong Y (2014) Activated microglia in the spinal cord underlies diabetic neuropathic pain. Eur J Pharmacol 728:59–66

    Article  CAS  PubMed  Google Scholar 

  166. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ji RR, Berta T, Nedergaard M (2013) Glia and pain: is chronic pain a gliopathy? Pain 154(Suppl 1):S10–S28

    Article  PubMed  PubMed Central  Google Scholar 

  168. Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD et al (2003) Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86:1534–1544

    Article  CAS  PubMed  Google Scholar 

  169. Ji RR, Suter MR (2007) P38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 3:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Tanga FY, Nutile-McMenemy N, De Leo JA (2005) The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 102:5856–5861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, Choi SY et al (2007) A critical role of Toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 282:14975–14983

    Article  CAS  PubMed  Google Scholar 

  172. Obata K, Katsura H, Miyoshi K, Kondo T, Yamanaka H, Kobayashi K et al (2008) Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury. J Neurochem 105:2249–2259

    Article  CAS  PubMed  Google Scholar 

  173. Scholz J, Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells, and glia. Nature Neurosci 10:1361–1368

    Article  CAS  PubMed  Google Scholar 

  174. Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in ‘small’ glia. Trends Neurosci 28:101–107

    Article  CAS  PubMed  Google Scholar 

  175. Ashton JC, Glass M (2007) The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 5:73–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nature Rev Drug Discov 2:973–985

    Article  CAS  Google Scholar 

  177. Romero-Sandoval EA, Horvath RJ, Deleo JA (2008) Neuroimmune interactions and pain: focus on glial modulating targets. Curr Opin Investig Drugs 9:726–734

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Financial support from the Department of Biotechnology and Indian Council of Medical Research, New Delhi is thankfully acknowledged. Aarti Nagayach is an Indian Council of Medical Research (ICMR) Senior Research Fellow. Facilities developed through the DBT-Human Resource Development and Bioinformatics Infrastructural facility through Department of Biotechnology Grants used in this study are thankfully acknowledged.

Conflict of interest

Authors have no conflict of interest.

Author information

Authors and Affiliations

  1. School of Studies in Neuroscience, Jiwaji University, Gwalior, 474011, Madhya Pradesh, India

    Aarti Nagayach, Nisha Patro & Ishan Patro

  2. School of Studies in Zoology, Jiwaji University, Gwalior, 474011, Madhya Pradesh, India

    Ishan Patro

Authors
  1. Aarti Nagayach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nisha Patro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ishan Patro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ishan Patro.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagayach, A., Patro, N. & Patro, I. Microglia in the Physiology and Pathology of Brain. Proc. Natl. Acad. Sci., India, Sect. B Biol. Sci. 86, 781–794 (2016). https://doi.org/10.1007/s40011-015-0585-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40011-015-0585-y

Keywords

Search

Navigation