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Microglia Function in the Normal Brain

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Glial Cells in Health and Disease of the CNS

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 949))

Abstract

The activation of microglia has been recognized for over a century by their morphological changes. Long slender microglia acquire a short sturdy ramified shape when activated. During the past 20 years, microglia have been accepted as an essential cellular component for understanding the pathogenic mechanism of many brain diseases, including neurodegenerative diseases. More recently, functional studies and imaging in mouse models indicate that microglia are active in the healthy central nervous system. It has become evident that microglia release several signal molecules that play key roles in the crosstalk among brain cells, i.e., astrocytes and oligodendrocytes with neurons, as well as with regulatory immune cells. Recent studies also reveal the heterogeneous nature of microglia diverse functions depending on development, previous exposure to stimulation events, brain region of residence, or pathological state. Subjects to approach by future research are still the unresolved questions regarding the conditions and mechanisms that render microglia protective, capable of preventing or reducing damage, or deleterious, capable of inducing or facilitating the progression of neuropathological diseases. This novel knowledge will certainly change our view on microglia as therapeutic target, shifting our goal from their general silencing to the generation of treatments able to change their activation pattern.

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Abbreviations

5-HT:

Serotonin

Aβ:

β-amyloid

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ATP:

Adenosine triphosphate

BDNF:

Brain derived neurotrophic factor

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

DAMPs:

Damage- or Danger-associated molecular patterns

EP2:

Prostanoid receptor subtype 2

GABA:

Gamma aminobutyric acid

GDNF:

Glia derived neurotrophic factor

GM-CSF:

Granulocyte/macrophage colony stimulating factor

HIV-1:

 Human immunodeficiency virus

IFNγ:

 Interferon gamma

IGF1:

Insulin-like growth factor 1

IL1:

Interleukin 1

iNOS:

Inducible nitric oxide synthase

InsP3:

Inositol trisphosphate

LPS:

Lipopolysaccharides

LTP:

Long time Potentiation

M-CSF:

Macrophage colony-stimulating factor

MHC:

Class I molecules of histocompatibility major complex

NGF:

Nerve growth factor

NMDA:

N-methyl-d-aspartate

NO:

Nitric Oxide

NT:

Neurotrophin

PAMPs:

Pathogen-associated molecular patterns

PGE2:

Prostaglandin E2

PRRs:

Pattern recognition receptors

RANTES:

Regulated on activation, normal T cell expressed and secreted—chemokine CCL5

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

Rs:

Receptors

SDF-1α:

Stromal cell-derived factor

SIRPα:

Signal regulatory protein α

SRs:

Scavenger receptors

TGFβ:

Transforming growth factor-β

TLRs:

Toll-like receptors

TNFα:

Tumor necrosis factor α

TSPs:

Thrombospondins

References

  • Aarum J, Sandberg K, Haeberlein SL, Persson MA (2003) Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci USA 100(26):15983–15988. doi:10.1073/pnas.2237050100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10(12):1538–1543. doi:10.1038/nn2014

    Article  CAS  PubMed  Google Scholar 

  • Alarcón R, Fuenzalida C, Santibanez M, von Bernhardi R (2005) Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound beta-amyloid. J Biol Chem 280(34):30406–30415. doi:10.1074/jbc.M414686200

    Google Scholar 

  • Aravalli RN, Hu S, Lokensgard JR (2007a) Toll-like receptor 2 signaling is a mediator of apoptosis in herpes simplex virus-infected microglia. J Neuroinflammation 4:11. doi:10.1186/1742-2094-4-11

    Article  PubMed  PubMed Central  Google Scholar 

  • Aravalli RN, Hu S, Lokensgard JR (2008) Inhibition of toll-like receptor signaling in primary murine microglia. J Neuroimmu Pharmacol Off J Soc NeuroImmu Pharmacol 3(1):5–11. doi:10.1007/s11481-007-9097-8

    Article  Google Scholar 

  • Aravalli RN, Peterson PK, Lokensgard JR (2007b) Toll-like receptors in defense and damage of the central nervous system. J Neuroimmu Pharmacol Off J Soc NeuroImmu Pharmacol 2(4):297–312. doi:10.1007/s11481-007-9071-5

    Article  Google Scholar 

  • Areschoug T, Gordon S (2009) Scavenger receptors: role in innate immunity and microbial pathogenesis. Cell Microbiol 11(8):1160–1169. doi:10.1111/j.1462-5822.2009.01326.x

    Article  CAS  PubMed  Google Scholar 

  • Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, Yirmiya R (2003) Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 13:826–834

    Google Scholar 

  • Babcock AA, Wirenfeldt M, Holm T, Nielsen HH, Dissing-Olesen L, Toft-Hansen H, Millward JM, Landmann R, Rivest S, Finsen B, Owens T (2006) Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation. J Neurosci 26(49):12826–12837. doi:10.1523/JNEUROSCI.4937-05.2006

    Article  CAS  PubMed  Google Scholar 

  • Barclay AN, Wright GJ, Brooke G, Brown MH (2002) CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23(6):285–290

    Article  CAS  PubMed  Google Scholar 

  • Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295:2282–2285

    Google Scholar 

  • Ben-Hur T, Ben-Menachem O, Furer V, Einstein O, Mizrachi-Kol R, Grigoriadis N (2003) Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells. Mol Cell Neurosci 24:623–631  

    Google Scholar 

  • Beurel E, Michalek SM, Jope RS (2010) Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 31(1):24–31. doi:10.1016/j.it.2009.09.007

    Article  CAS  PubMed  Google Scholar 

  • Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4(7):702–710. doi:10.1038/89490

    Article  CAS  PubMed  Google Scholar 

  • Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81(1):1–5. doi:10.1189/jlb.0306164

    Article  CAS  PubMed  Google Scholar 

  • Biber K, Neumann H, Inoue K, Boddeke HW (2007) Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30(11):596–602. doi:10.1016/j.tins.2007.08.007

    Article  CAS  PubMed  Google Scholar 

  • Biber K, Vinet J, Boddeke HW (2008) Neuron-microglia signaling: chemokines as versatile messengers. J Neuroimmunol 198(1–2):69–74. doi:10.1016/j.jneuroim.2008.04.012

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76(2):77–98. doi:10.1016/j.pneurobio.2005.06.004

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Li G, Qin L , Wu X, Pei Z, Wang T et al (2006) Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin. FASEB J 20:251–258  

    Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69. doi:10.1038/nrn2038

    Article  CAS  PubMed  Google Scholar 

  • Boucsein C, Zacharias R, Farber K, Pavlovic S, Hanisch UK, Kettenmann H (2003) Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci 17(11):2267–2276

    Article  PubMed  Google Scholar 

  • Brooke G, Holbrook JD, Brown MH, Barclay AN (2004) Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family. J Immunol 173(4):2562–2570

    Article  CAS  PubMed  Google Scholar 

  • Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31(1):149–160. doi:10.1016/j.mcn.2005.10.006

    Article  CAS  PubMed  Google Scholar 

  • Carbonell WS, Murase S, Horwitz AF, Mandell JW (2005) Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5: an in situ time-lapse confocal imaging study. J Neurosci 25(30):7040–7047. doi:10.1523/JNEUROSCI.5171-04.2005

    Article  CAS  PubMed  Google Scholar 

  • Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924. doi:10.1038/nn1715

    Article  CAS  PubMed  Google Scholar 

  • Carpentier PA, Duncan DS, Miller SD (2008) Glial toll-like receptor signaling in central nervous system infection and autoimmunity. Brain Behav Immun 22(2):140–147. doi:10.1016/j.bbi.2007.08.011

    Article  CAS  PubMed  Google Scholar 

  • Casano AM, Peri F (2015) Microglia: multitasking specialists of the brain. Dev Cell 32(4):469–477. doi:10.1016/j.devcel.2015.01.018

    Article  CAS  PubMed  Google Scholar 

  • Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115(12):1599–1608. doi:10.1161/CIRCULATIONAHA.106.603431

    Article  CAS  PubMed  Google Scholar 

  • Cepko CL, Austin CP, Yang X, Alexiades M, Ezzeddine D (1996) Cell fate determination in the vertebrate retina. Proc Natl Acad Sci USA 93:589–595

    Google Scholar 

  • Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C (2010) Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving forcé for amyloid deposition. FASEB J 24:548–559

    Google Scholar 

  • Chamak B, Dobbertin A, Mallat M (1995) Immunohistochemical detection of thrombospondin in microglia in the developing rat brain. Neuroscience 69:177–187

    Google Scholar 

  • Chang YP, Fang KM, Lee TI, Tzeng SF (2006) Regulation of microglial activities by glial cell line derived neurotrophic factor. J Cell Biochem 97(3):501–511. doi:10.1002/jcb.20646

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Trapp BD (2015) Microglia and neuroprotection. J Neurochem. doi:10.1111/jnc.13062

    Google Scholar 

  • Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98. doi:10.1186/1742-2094-11-98

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433. doi:10.1016/j.cell.2004.12.020

    Article  CAS  PubMed  Google Scholar 

  • Colton C, Wilcock DM (2010) Assessing activation states in microglia. CNS Neurol Disord: Drug Targets 9(2):174–191

    Article  CAS  Google Scholar 

  • Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmu Pharmacol Off J Soc NeuroImmun Pharmacol 4(4):399–418. doi:10.1007/s11481-009-9164-4

    Article  Google Scholar 

  • Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65(3):199–203. doi:10.1097/01.jnen.0000202887.22082.63

    Article  PubMed  Google Scholar 

  • Cornejo F, von Bernhardi R (2013) Role of scavenger receptors in glia-mediated neuroinflammatory response associated with Alzheimer’s disease. Mediat Inflamm 2013:895651. doi:10.1155/2013/895651

    Article  Google Scholar 

  • Corriveau RA, Huh GS, Shatz CJ (1998) Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21:505–520

    Google Scholar 

  • Cullheim S, Thams S (2007) The microglial networks of the brain and their role in neuronal network plasticity after lesion. Brain Res Rev 55(1):89–96. doi:10.1016/j.brainresrev.2007.03.012

    Article  CAS  PubMed  Google Scholar 

  • Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758. doi:10.1038/nn1472

    Article  CAS  PubMed  Google Scholar 

  • Davoust N, Vuaillat C, Androdias G, Nataf S (2008) From bone marrow to microglia: barriers and avenues. Trends Immunol 29(5):227–234. doi:10.1016/j.it.2008.01.010

    Article  CAS  PubMed  Google Scholar 

  • Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P (2010) Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimers Dis 20(Suppl 2):S369–S379. doi:10.3233/JAD-2010-100543

    PubMed  Google Scholar 

  • Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 100(23):13632–13637. doi:10.1073/pnas.2234031100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ekdahl CT, Kokaia Z, Lindvall O (2009) Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 158(3):1021–1029. doi:10.1016/j.neuroscience.2008.06.052

    Article  CAS  PubMed  Google Scholar 

  • Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16(8):2508–2521

    CAS  PubMed  Google Scholar 

  • Fang KM, Yang CS, Sun SH, Tzeng SF (2009) Microglial phagocytosis attenuated by short-term exposure to exogenous ATP through P2X receptor action. J Neurochem 111(5):1225–1237. doi:10.1111/j.1471-4159.2009.06409.x

    Article  CAS  PubMed  Google Scholar 

  • Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K (2004) The LPS receptor (CD14) links innate immunity with Alzheimer’s disease. FASEB J 18(1):203–205. doi:10.1096/fj.03-0364fje

    CAS  PubMed  Google Scholar 

  • Fenn AM, Hall JC, Gensel JC, Popovich PG, Godbout JP (2014) IL-4 signaling drives a unique arginase+/IL-1beta+microglia phenotype and recruits macrophages to the inflammatory CNS: consequences of age-related deficits in IL-4Ralpha after traumatic spinal cord injury. J Neurosci 34(26):8904–8917. doi:10.1523/JNEUROSCI.1146-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrini F, De Koninck Y (2013) Microglia control neuronal network excitability via BDNF signalling. Neural Plast 2013:429815. doi:10.1155/2013/429815

    PubMed  PubMed Central  Google Scholar 

  • Flores B, von Bernhardi R (2012) Transforming growth factor beta1 modulates amyloid beta-induced glial activation through the Smad3-dependent induction of MAPK phosphatase-1. J Alzheimer Dis 32(2):417–429. doi:10.3233/JAD-2012-120721 Y05258137G173L5 V[pii]

    CAS  Google Scholar 

  • Frade JM, Barde YA (1998) Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20(1):35–41

    Article  CAS  PubMed  Google Scholar 

  • Gamo K, Kiryu-Seo S, Konishi H, Aoki S, Matsushima K, Wada K, Kiyama H (2008) G-protein-coupled receptor screen reveals a role for chemokine receptor CCR5 in suppressing microglial neurotoxicity. J Neurosci 28(46):11980–11988. doi:10.1523/JNEUROSCI.2920-08.2008

    Article  CAS  PubMed  Google Scholar 

  • Gavilan MP, Revilla E, Pintado C, Castano A, Vizuete ML, Moreno-Gonzalez I, Baglietto-Vargas D, Sanchez-Varo R, Vitorica J, Gutierrez A, Ruano D (2007) Molecular and cellular characterization of the age-related neuroinflammatory processes occurring in normal rat hippocampus: potential relation with the loss of somatostatin GABAergic neurons. J Neurochem 103(3):984–996. doi:10.1111/j.1471-4159.2007.04787.x

    Article  CAS  PubMed  Google Scholar 

  • Gebicke-Haerter PJ, Spleiss O, Ren LQ, Li H, Dichmann S, Norgauer J, Boddeke HW (2001) Microglial chemokines and chemokine receptors. Prog Brain Res 132:525–532. doi:10.1016/S0079-6123(01)32100-3

    Article  CAS  PubMed  Google Scholar 

  • Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. doi:10.1126/science.1194637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giulian D, Young DG, Woodward J, Brown DC, Lachman LB (1988) Interleukin-1 is an astroglial growth factor in the developing brain. J Neurosci 8(2):709–714

    CAS  PubMed  Google Scholar 

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934. doi:10.1016/j.cell.2010.02.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glezer I, Simard AR, Rivest S (2007) Neuroprotective role of the innate immune system by microglia. Neuroscience 147(4):867–883. doi:10.1016/j.neuroscience.2007.02.055

    Article  CAS  PubMed  Google Scholar 

  • Goddard CA, Butts DA, Shatz CJ (2007) Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci USA 104:6828–6833

    Google Scholar 

  • Godoy B, Murgas P, Tichauer J, Von Bernhardi R (2012) Scavenger receptor class A ligands induce secretion of IL1beta and exert a modulatory effect on the inflammatory activation of astrocytes in culture. J Neuroimmunol 251(1–2):6–13. doi:10.1016/j.jneuroim.2012.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T, Levy-Lahad E, Yirmiya R (2007) A dual role for interleukin-1 in hippocampal dependent memory processes. Psychoneuroendocrinology 32:1106–1115

    Google Scholar 

  • Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119(1):89–105. doi:10.1007/s00401-009-0622-0

    Article  PubMed  Google Scholar 

  • Hanisch UK, Johnson TV, Kipnis J (2008) Toll-like receptors: roles in neuroprotection? Trends Neurosci 31(4):176–182. doi:10.1016/j.tins.2008.01.005

    Article  CAS  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi:10.1038/nn1997

    Article  CAS  PubMed  Google Scholar 

  • Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9(12):1512–1519. doi:10.1038/nn1805

    Article  CAS  PubMed  Google Scholar 

  • Hellwig S, Heinrich A, Biber K (2013) The brain’s best friend: microglial neurotoxicity revisited. Front Cell Neurosci 7:71. doi:10.3389/fncel.2013.00071

    Article  PubMed  PubMed Central  Google Scholar 

  • Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer’s disease. Nat Immunol 16(3):229–236. doi:10.1038/ni.3102

    Article  CAS  PubMed  Google Scholar 

  • Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev 14(7):463–477. doi:10.1038/nri3705

    CAS  Google Scholar 

  • Herrera-Molina R, Flores B, Orellana JA, von Bernhardi R (2012) Modulation of interferon-gamma-induced glial cell activation by transforming growth factor beta1: a role for STAT1 and MAPK pathways. J Neurochem 123(1):113–123. doi:10.1111/j.1471-4159.2012.07887.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herrera-Molina R, von Bernhardi R (2005) Transforming growth factor-beta 1 produced by hippocampal cells modulates microglial reactivity in culture. Neurobiol Dis 19(1–2):229–236. doi:10.1016/j.nbd.2005.01.003

    Article  CAS  PubMed  Google Scholar 

  • Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290(5497):1768–1771

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 11(1):56–64. doi:10.1038/nrneurol.2014.207

    Article  PubMed  Google Scholar 

  • Huh GS, Boulanger  LM, Du H, Riquelme PA, Brotz TM, Shatz CJ (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155–2159

    Google Scholar 

  • Ifuku M, Farber K, Okuno Y, Yamakawa Y, Miyamoto T, Nolte C, Merrino VF, Kita S, Iwamoto T, Komuro I, Wang B, Cheung G, Ishikawa E, Ooboshi H, Bader M, Wada K, Kettenmann H, Noda M (2007) Bradykinin-induced microglial migration mediated by B1-bradykinin receptors depends on Ca2+ influx via reverse-mode activity of the Na+/Ca2+ exchanger. J Neurosci 27(48):13065–13073. doi:10.1523/JNEUROSCI.3467-07.2007

    Article  CAS  PubMed  Google Scholar 

  • Inoue K, Koizumi S, Kataoka A, Tozaki-Saitoh H, Tsuda M (2009) P2Y(6)-evoked microglial phagocytosis. Int Rev Neurobiol 85:159–163. doi:10.1016/S0074-7742(09)85012-5

    Article  CAS  PubMed  Google Scholar 

  • Kempermann G (2002) Regulation of adult hippocampal neurogenesis—implications for novel theories of major depression. Bipolar Disord 4(1):17–33

    Article  PubMed  Google Scholar 

  • Kempermann G, Kronenberg G (2003) Depressed new neurons–adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol Psychiatry 54(5):499–503

    Article  PubMed  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553. doi:10.1152/physrev.00011.2010

    Article  CAS  PubMed  Google Scholar 

  • Kielian T, Esen N, Bearden ED (2005) Toll-like receptor 2 (TLR2) is pivotal for recognition of S. aureus peptidoglycan but not intact bacteria by microglia. Glia 49(4):567–576. doi:10.1002/glia.20144

    Google Scholar 

  • Kierdorf K, Katzmarski N, Haas CA, Prinz M (2013) Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS One 8(3):e58544. doi:10.1371/journal.pone.0058544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kierdorf K, Prinz M (2013) Factors regulating microglia activation. Front Cell Neurosci 7:44. doi:10.3389/fncel.2013.00044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81(3):302–313

    Article  CAS  PubMed  Google Scholar 

  • Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A (1995) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci 15:7861–7871

    Google Scholar 

  • Koenigsknecht J, Landreth G (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 24(44):9838–9846. doi:10.1523/JNEUROSCI.2557-04.2004

    Article  CAS  PubMed  Google Scholar 

  • Kohman RA, Bhattacharya TK, Kilby C, Bucko P, Rhodes JS (2013) Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice. Behav Brain Res 242:17–24. doi:10.1016/j.bbr.2012.12.032

    Article  CAS  PubMed  Google Scholar 

  • Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446(7139):1091–1095. doi:10.1038/nature05704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konat GW, Kielian T, Marriott I (2006) The role of Toll-like receptors in CNS response to microbial challenge. J Neurochem 99(1):1–12. doi:10.1111/j.1471-4159.2006.04076.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev 8(4):279–289. doi:10.1038/nri2215

    Article  CAS  Google Scholar 

  • Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105:751–756

    Google Scholar 

  • Kremlev SG, Roberts RL, Palmer C (2004) Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. J Neuroimmunol 149(1–2):1–9. doi:10.1016/j.jneuroim.2003.11.012

    Article  CAS  PubMed  Google Scholar 

  • Labrousse VF, Costes L, Aubert A, Darnaudery M, Ferreira G, Amedee T, Laye S (2009) Impaired interleukin-1beta and c-Fos expression in the hippocampus is associated with a spatial memory deficit in P2X(7) receptor-deficient mice. PLoS One 4:e6006

    Google Scholar 

  • Lalo U, Pankratov Y, Wichert SP, Rossner MJ, North RA, Kirchhoff F, Verkhratsky A (2008) P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J Neurosci 28:5473–5480

    Google Scholar 

  • Landreth GE, Reed-Geaghan EG (2009) Toll-like receptors in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153. doi:10.1007/978-3-642-00549-7_8

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee TI, Yang CS, Fang KM, Tzeng SF (2009) Role of ciliary neurotrophic factor in microglial phagocytosis. Neurochem Res 34(1):109–117. doi:10.1007/s11064-008-9682-0

    Article  CAS  PubMed  Google Scholar 

  • Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22(7):2478–2486. doi:20026268

  • Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G, Nitsch R, Weber JR (2008) A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 28(10):2320–2331. doi:10.1523/JNEUROSCI.4760-07.2008

    Article  CAS  PubMed  Google Scholar 

  • Lehnardt S, Wennekamp J, Freyer D, Liedtke C, Krueger C, Nitsch R, Bechmann I, Weber JR, Henneke P (2007) TLR2 and caspase-8 are essential for group B Streptococcus-induced apoptosis in microglia. J Immunol 179(9):6134–6143

    Article  CAS  PubMed  Google Scholar 

  • Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30(5):759–768. doi:10.1016/j.neurobiolaging.2007.08.018

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Du XF, Liu CS, Wen ZL, Du JL (2012) Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell 23(6):1189–1202. doi:10.1016/j.devcel.2012.10.027

    Article  CAS  PubMed  Google Scholar 

  • Liang X, Wang Q, Hand T, Wu L, Breyer RM, Montine TJ, Andreasson K (2005) Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer’s disease. J Neurosci 25(44):10180–10187. doi:10.1523/JNEUROSCI.3591-05.2005

    Article  CAS  PubMed  Google Scholar 

  • Liang KJ, Lee JE, Wang YD, Ma W, Fontainhas AM, Fariss RN, Wong WT (2009) Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. Investig Ophthalmol Vis Sci 50:4444–4451

    Google Scholar 

  • Lim SH, Park E, You B, Jung Y, Park AR, Park SG, Lee JR (2013) Neuronal synapse formation induced by microglia and interleukin 10. PLoS One 8:e81218 astrocytes. J Neurosci 28:5473–5480

    Google Scholar 

  • Linda H, Shupliakov O, Ornung G, Ottersen OP, Storm-Mathisen J, Risling M, Cullheim S (2000) Ultrastructural evidence for a preferential elimination of glutamate-immunoreactive synaptic terminals from spinal motoneurons after intramedullary axotomy. J Comp Neurol 425(1):10–23

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, Heine H, Penke B, Neumann H, Fassbender K (2005) LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 128(Pt 8):1778–1789. doi:10.1093/brain/awh531

    Article  PubMed  Google Scholar 

  • Loscher CE, Mills KH, Lynch MA (2003) Interleukin-1 receptor antagonist exerts agonist activity in the hippocampus independent of the interleukin-1 type I receptor. J Neuroimmunol 137:117–124

    Google Scholar 

  • Lotz M, Ebert S, Esselmann H, Iliev AI, Prinz M, Wiazewicz N, Wiltfang J, Gerber J, Nau R (2005) Amyloid beta peptide 1-40 enhances the action of Toll-like receptor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced inflammation in primary mouse microglial cell cultures. J Neurochem 94(2):289–298. doi:10.1111/j.1471-4159.2005.03188.x

    Article  CAS  PubMed  Google Scholar 

  • Lu C, Hua F, Liu L, Ha T, Kalbfleisch J, Schweitzer J, Kelley J, Kao R, Williams D, Li C (2010) Scavenger receptor class-A has a central role in cerebral ischemia-reperfusion injury. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 30(12):1972–1981. doi:10.1038/jcbfm.2010.59

    Article  CAS  Google Scholar 

  • Lynch MA (2009) The multifaceted profile of activated microglia. Mol Neurobiol 40(2):139–156. doi:10.1007/s12035-009-8077-9

    Article  CAS  PubMed  Google Scholar 

  • Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41(4):535–547

    Article  CAS  PubMed  Google Scholar 

  • Matozaki T, Murata Y, Okazawa H, Ohnishi H (2009) Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol 19(2):72–80. doi:10.1016/j.tcb.2008.12.001

    Article  CAS  PubMed  Google Scholar 

  • Matzinger P (2007) Friendly and dangerous signals: is the tissue in control? Nat Immunol 8(1):11–13. doi:10.1038/ni0107-11

    Article  CAS  PubMed  Google Scholar 

  • McKimmie CS, Fazakerley JK (2005) In response to pathogens, glial cells dynamically and differentially regulate Toll-like receptor gene expression. J Neuroimmunol 169(1–2):116–125. doi:10.1016/j.jneuroim.2005.08.006

    Article  CAS  PubMed  Google Scholar 

  • McPherson CA, Kraft AD, Harry GJ (2011) Injury-induced neurogenesis: consideration of resident microglia as supportive of neural progenitor cells. Neurotox Res 19(2):341–352. doi:10.1007/s12640-010-9199-6

    Article  PubMed  Google Scholar 

  • Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10(12):1544–1553. doi:10.1038/nn2015

    Article  CAS  PubMed  Google Scholar 

  • Mitrasinovic OM, Murphy GM Jr (2002) Accelerated phagocytosis of amyloid-B by mouse and human microglia overexpressing the macrophage colony-stimulating factor receptor. J Biol Chem 277:29889–29896

    Google Scholar 

  • Mitrasinovic OM, Murphy GM Jr (2003) Microglial overexpression of the M-CSF receptor augments phagocytosis of opsonized Abeta. Neurobiol Aging 24(6):807–815

    Article  CAS  PubMed  Google Scholar 

  • Moller JC, Klein MA, Haas S, Jones LL, Kreutzberg GW, Raivich G (1996) Regulation of thrombospondin in the regenerating mouse facial motor nucleus. Glia 17(2):121–132. doi:10.1002/(SICI)1098-1136(199606)17:2<121:AID-GLIA4>3.0.CO;2-5

    Article  CAS  PubMed  Google Scholar 

  • Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760–1765. doi:10.1126/science.1088417

    Article  CAS  PubMed  Google Scholar 

  • Morgan SC, Taylor DL, Pocock JM (2004) Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades. J Neurochem 90(1):89–101. doi:10.1111/j.1471-4159.2004.02461.x

    Article  CAS  PubMed  Google Scholar 

  • Mount MP, Lira A, Grimes D, Smith PD, Faucher S, Slack R, et al (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. J Neurosci 27:3328–3337

    Google Scholar 

  • Murgas P, Cornejo FA, Merino G, von Bernhardi R (2014) SR-A regulates the inflammatory activation of astrocytes. Neurotox Res 25(1):68–80. doi:10.1007/s12640-013-9432-1

    Article  CAS  PubMed  Google Scholar 

  • Murgas P, Godoy B, von Bernhardi R (2012) Abeta potentiates inflammatory activation of glial cells induced by scavenger receptor ligands and inflammatory mediators in culture. Neurotox Res 22(1):69–78. doi:10.1007/s12640-011-9306-3

    Article  CAS  PubMed  Google Scholar 

  • Nakajima Y, Tohyama T, Kurihara S, Kohsaka S (2005) Axotomy-dependent urokinase induction in the rat facial nucleus: possible stimulation of microglia by neurons. Neurochem Int 46:107–116

    Google Scholar 

  • Nakajima K, Tohyama Y, Maeda S, Kohsaka S, Kurihara T (2007) Neuronal regulation by which microglia enhance the production of neurotrophic factors for GABAergic, catecholaminergic, and cholinergic neurons. Neurochem Int 50:807–820

    Google Scholar 

  • Nakanishi M, Niidome T, Matsuda S, Akaike A, Kihara T, Sugimoto H (2007) Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci 25(3):649–658. doi:10.1111/j.1460-9568.2007.05309.x

    Article  PubMed  Google Scholar 

  • Napoli I, Neumann H (2009) Microglial clearance function in health and disease. Neuroscience 158(3):1030–1038. doi:10.1016/j.neuroscience.2008.06.046

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132(Pt 2):288–295. doi:10.1093/brain/awn109

    CAS  PubMed  Google Scholar 

  • Nguyen MD, D’Aigle T, Gowing G, Julien JP, Rivest S (2004) Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J Neurosci 24(6):1340–1349. doi:10.1523/JNEUROSCI.4786-03.2004

    Article  CAS  PubMed  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. doi:10.1126/science.1110647

    Article  CAS  PubMed  Google Scholar 

  • Ock J, Jeong J, Choi WS, Lee WH, Kim SH, Kim IK, Suk K (2007) Regulation of Toll-like receptor 4 expression and its signaling by hypoxia in cultured microglia. J Neurosci Res 85(9):1989–1995. doi:10.1002/jnr.21322

    Article  CAS  PubMed  Google Scholar 

  • Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59(2):278–292. doi:10.1016/j.brainresrev.2008.09.001

    Article  CAS  PubMed  Google Scholar 

  • Oliveira AL, Thams S, Lidman O, Piehl F, Hökfelt T, Kärre K, Lindå H, Cullheim S (2004) A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci USA 101(51):17843–17848

    Google Scholar 

  • Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173:3916–3924

    Google Scholar 

  • Orellana JA, Montero TD, von Bernhardi R (2013) Astrocytes inhibit nitric oxide-dependent Ca(2+) dynamics in activated microglia: involvement of ATP released via pannexin 1 channels. Glia 61(12):2023–2037. doi:10.1002/glia.22573

    Article  PubMed  Google Scholar 

  • Ozeki Y, Tsutsui H, Kawada N, Suzuki H, Kataoka M, Kodama T, Yano I, Kaneda K, Kobayashi K (2006) Macrophage scavenger receptor down-regulates mycobacterial cord factor-induced proinflammatory cytokine production by alveolar and hepatic macrophages. Microb Pathog 40(4):171–176. doi:10.1016/j.micpath.2005.12.006

    Article  CAS  PubMed  Google Scholar 

  • Padovan E, Landmann RM, De Libero G (2007) How pattern recognition receptor triggering influences T cell responses: a new look into the system. Trends Immunol 28(7):308–314. doi:10.1016/j.it.2007.05.002

    Article  CAS  PubMed  Google Scholar 

  • Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456–1458. doi:10.1126/science.1202529

    Article  CAS  PubMed  Google Scholar 

  • Paolicelli RC, Gross CT (2011) Microglia in development: linking brain wiring to brain environment. Neuron Glia Biol 7(1):77–83. doi:10.1017/S1740925X12000105

    Article  PubMed  Google Scholar 

  • 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. doi:10.1016/j.cell.2013.11.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev 7(2):161–167. doi:10.1038/nri2015 nri2015[pii]

    CAS  Google Scholar 

  • Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nature reviews Neurology 10(4):217–224. doi:10.1038/nrneurol.2014.38

    Article  CAS  PubMed  Google Scholar 

  • Pocock JM, Kettenmann H (2007) Neurotransmitter receptors on microglia. Trends Neurosci 30(10):527–535. doi:10.1016/j.tins.2007.07.007

    Article  CAS  PubMed  Google Scholar 

  • Prinz M, Priller J (2010) Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J Neuroimmunol 224(1–2):80–84. doi:10.1016/j.jneuroim.2010.05.015

    Article  CAS  PubMed  Google Scholar 

  • 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. doi:10.1038/nrn3722

    Article  CAS  PubMed  Google Scholar 

  • Ramírez G, Rey S, von Bernhardi R (2008) Proinflammatory stimuli are needed for induction of microglial cell-mediated AbetaPP_{244-C} and Abeta-neurotoxicity in hippocampal cultures. J Alzheimer Dis 15(1):45–59

    Google Scholar 

  • Ramirez G, Toro R, Dobeli H, von Bernhardi R (2005) Protection of rat primary hippocampal cultures from A beta cytotoxicity by pro-inflammatory molecules is mediated by astrocytes. Neurobiol Dis 19(1–2):243–254. doi:10.1016/j.nbd.2005.01.007

    Article  CAS  PubMed  Google Scholar 

  • Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C, Kovac AD, Gerard C, Boddeke HW, Nitsch R, Kettenmann H (2004) CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci 24(39):8500–8509. doi:10.1523/JNEUROSCI.2451-04.2004

    Article  CAS  PubMed  Google Scholar 

  • Rappert A, Biber K, Nolte C, Lipp M, Schubel A, Lu B, Gerard NP, Gerard C, Boddeke HW, Kettenmann H (2002) Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl- current and chemotaxis in murine microglia. J Immunol 168(7):3221–3226

    Article  CAS  PubMed  Google Scholar 

  • Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 29(38):11982–11992. doi:10.1523/JNEUROSCI.3158-09.2009 29/38/11982[pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ribeiro Xavier AL, Kress BT, Goldman SA, Lacerda de Menezes JR, Nedergaard M (2015) A distinct population of microglia supports adult neurogenesis in the subventricular zone. J Neurosci 35(34):11848–11861. doi:10.1523/JNEUROSCI.1217-15.2015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rogers  JT, Morganti JM, Bachstetter AD, Hudson CE, Peters  MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 31:16241–16250

    Google Scholar 

  • Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9:1081–1088

    Google Scholar 

  • Roumier A, Bechade C, Poncer JC, Smalla KH, Tomasello E, Vivier E, Gundelfinger ED, Triller A, Bessis A (2004) Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 24:11421–11428

    Google Scholar 

  • Rubartelli A, Lotze MT (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol 28(10):429–436. doi:10.1016/j.it.2007.08.004

    Article  CAS  PubMed  Google Scholar 

  • 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 74:691–705

    Google Scholar 

  • Schaffler A, Scholmerich J, Salzberger B (2007) Adipose tissue as an immunological organ: Toll-like receptors, C1q/TNFs and CTRPs. Trends Immunol 28(9):393–399. doi:10.1016/j.it.2007.07.003

    Article  CAS  PubMed  Google Scholar 

  • Schilling T, Nitsch R, Heinemann U, Haas D, Eder C (2001) Astrocyte-released cytokines induce ramification and outward K+ channel expression in microglia via distinct signalling pathways. Eur J Neurosci 14(3):463–473

    Article  CAS  PubMed  Google Scholar 

  • Schilling T, Stock C, Schwab A, Eder C (2004) Functional importance of Ca2+-activated K+ channels for lysophosphatidic acid-induced microglial migration. Eur J Neurosci 19(6):1469–1474. doi:10.1111/j.1460-9568.2004.03265.x

    Article  PubMed  Google Scholar 

  • Schmid AW, Lynch MA, Herron CE (2009) The effects of IL-1 receptor antagonist on beta amyloid mediated depression of LTP in the rat CA1 in vivo. Hippocampus 19:670–676

    Google Scholar 

  • Schwab A (2001) Ion channels and transporters on the move. News Physiol Sci Int J Physiol Produc Join Int Union Physiol Sci Am Physiol Soc 16:29–33

    CAS  Google Scholar 

  • Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29(2):68–74. doi:10.1016/j.tins.2005.12.005

    Article  CAS  PubMed  Google Scholar 

  • Sedel F, Bechade C, Vyas S, Triller A (2004) Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J Neurosci 24(9):2236–2246. doi:10.1523/JNEUROSCI.4464-03.2004

    Article  CAS  PubMed  Google Scholar 

  • Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6(7):e1000113. doi:10.1371/journal.pmed.1000113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shie FS, Breyer RM, Montine TJ (2005) Microglia lacking E prostanoid receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity. Am J Pathol 166(4):1163–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K (2014) Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci 34:2231–2243

    Google Scholar 

  • Sievers J, Schmidtmayer J, Parwaresch R (1994) Blood monocytes and spleen macrophages differentiate into microglia-like cells when cultured on astrocytes. Ann Anat Anatom Anz Off Organ Anatom Ges 176(1):45–51

    Google Scholar 

  • Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49(4):489–502. doi:10.1016/j.neuron.2006.01.022

    Article  CAS  PubMed  Google Scholar 

  • Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33(3):256–266

    Article  CAS  PubMed  Google Scholar 

  • Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131(6):1164–1178. doi:10.1016/j.cell.2007.10.036

    Article  CAS  PubMed  Google Scholar 

  • Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–161. doi:10.1038/ni.1836

    Article  CAS  PubMed  Google Scholar 

  • Streit WJ, Conde JR, Fendrick SE, Flanary BE, Mariani CL (2005) Role of microglia in the central nervous system’s immune response. Neurol Res 27(7):685–691. doi:10.1179/016164105X49463

    PubMed  Google Scholar 

  • Syed MM, Phulwani NK, Kielian T (2007) Tumor necrosis factor-alpha (TNF-alpha) regulates Toll-like receptor 2 (TLR2) expression in microglia. J Neurochem 103(4):1461–1471. doi:10.1111/j.1471-4159.2007.04838.x

    Article  CAS  PubMed  Google Scholar 

  • Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129(Pt 11):3006–3019. doi:10.1093/brain/awl249

    Article  PubMed  PubMed Central  Google Scholar 

  • Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83(5):1131–1143. doi:10.1016/j.neuron.2014.07.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tichauer J, Saud K, von Bernhardi R (2007) Modulation by astrocytes of microglial cell-mediated neuroinflammation: effect on the activation of microglial signaling pathways. NeuroImmunoModulation 14(3–4):168–174

    Article  CAS  PubMed  Google Scholar 

  • Tichauer JE, Flores B, Soler B, Eugenin-von Bernhardi L, Ramirez G, von Bernhardi R (2014) Age-dependent changes on TGFbeta1 Smad3 pathway modify the pattern of microglial cell activation. Brain Behav Immun 37:187–196. doi:10.1016/j.bbi.2013.12.018

    Article  CAS  PubMed  Google Scholar 

  • Tichauer JE, von Bernhardi R (2012) Transforming growth factor-beta stimulates beta amyloid uptake by microglia through Smad3-dependent mechanisms. J Neurosci Res 90(10):1970–1980. doi:10.1002/jnr.23082

    Article  CAS  PubMed  Google Scholar 

  • Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff R (2007) Evidence for synaptic stripping by cortical microglia. Glia 55(4):360–368. doi:10.1002/glia.20462

    Article  PubMed  Google Scholar 

  • Trebst C, Konig F, Ransohoff R, Bruck W, Stangel M (2008) CCR5 expression on macrophages/microglia is associated with early remyelination in multiple sclerosis lesions. Mult Scler 14(6):728–733. doi:10.1177/1352458508089359

    Article  CAS  PubMed  Google Scholar 

  • Umemori H, Sanes JR (2008) Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules. J Biol Chem 283(49):34053–34061. doi:10.1074/jbc.M805729200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Rossum D, Hanisch UK (2004) Microglia. Metab Brain Dis 19(3–4):393–411

    Article  PubMed  Google Scholar 

  • van Weering HR, Boddeke HW, Vinet J, Brouwer N, de Haas AH, van Rooijen N, Thomsen AR, Biber KP (2011) CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus. Hippocampus 21(2):220–232. doi:10.1002/hipo.20742

    Article  PubMed  CAS  Google Scholar 

  • von Bernhardi R (2007) Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotox Res 12(4):215–232

    Article  Google Scholar 

  • von Bernhardi R, Cornejo F, Parada GE, Eugenin J (2015a) Role of TGFbeta signaling in the pathogenesis of Alzheimer’s disease. Front Cell Neurosci 9:426. doi:10.3389/fncel.2015.00426

    Google Scholar 

  • von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J (2015b) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. doi:10.3389/fnagi.2015.00124

    Google Scholar 

  • von Bernhardi R, Eugenin J (2004) Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res 1–2:186–193. doi:10.1016/j.brainres.2004.07.084 (1025)

    Article  CAS  Google Scholar 

  • von Bernhardi R, Eugenin J (2012) Alzheimer’s disease: redox dysregulation as a common denominator for diverse pathogenic mechanisms. Antioxid Redox Signal 16(9):974–1031. doi:10.1089/ars.2011.4082

    Article  CAS  Google Scholar 

  • von Bernhardi R, Ramírez G (2001) Microglia-astrocyte interaction in Alzheimer’s disease: friends or foes for the nervous system? Biol Res 34(2):123–128

    Google Scholar 

  • von Bernhardi R, Tichauer JE, Eugenin J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112(5):1099–1114. doi:10.1111/j.1471-4159.2009.06537.x

    Article  CAS  Google Scholar 

  • 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. doi:10.1523/JNEUROSCI.4363-08.2009

    Article  CAS  PubMed  Google Scholar 

  • Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23(4):1398–1405

    CAS  PubMed  Google Scholar 

  • Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 20(6):947–956. doi:10.1159/000110455

    Article  CAS  Google Scholar 

  • Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP 2nd, Scheffler B, Steindler DA (2006) Microglia instruct subventricular zone neurogenesis. Glia 54(8):815–825. doi:10.1002/glia.20419

    Article  PubMed  Google Scholar 

  • Webster SD, Yang AJ, Margol L, Garzon-Rodriguez W, Glabe CG, Tenner AJ (2000) Complement component C1q modulates the phagocytosis of Abeta by microglia. Exp Neurol 161(1):127–138. doi:10.1006/exnr.1999.7260

    Article  CAS  PubMed  Google Scholar 

  • Witting A, Muller P, Herrmann A, Kettenmann H, Nolte C (2000) Phagocytic clearance of apoptotic neurons by Microglia/Brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition. J Neurochem 75(3):1060–1070

    Article  CAS  PubMed  Google Scholar 

  • Yirmiya R, Rimmerman N, Reshef R (2015) Depression as a microglial disease. Trends Neurosci 38(10):637–658. doi:10.1016/j.tins.2015.08.001

    Article  CAS  PubMed  Google Scholar 

  • Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D, Gross CT (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17(3):400–406. doi:10.1038/nn.3641

    Article  CAS  PubMed  Google Scholar 

  • Ziegler G, Harhausen D, Schepers C, Hoffmann O, Rohr C, Prinz V, Konig J, Lehrach H, Nietfeld W, Trendelenburg G (2007) TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 359(3):574–579. doi:10.1016/j.bbrc.2007.05.157

    Article  CAS  PubMed  Google Scholar 

  • Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9(2):268–275. doi:10.1038/nn1629

    Article  CAS  PubMed  Google Scholar 

  • Ziv Y, Schwartz M (2008) Immune-based regulation of adult neurogenesis: implications for learning and memory. Brain Behav Immun 22(2):167–176. doi:10.1016/j.bbi.2007.08.006

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grant FONDECYT 1131025 to RvB.

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Authors and Affiliations

  1. Escuela de Medicina. Departamento de Neurología, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, Chile

    Rommy von Bernhardi, Florencia Heredia, Nicole Salgado & Paola Muñoz

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  1. Rommy von Bernhardi
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  2. Florencia Heredia
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  3. Nicole Salgado
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  4. Paola Muñoz
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Correspondence to Rommy von Bernhardi .

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  1. Faculty of Medicine Professor of Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile

    Rommy von Bernhardi

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von Bernhardi, R., Heredia, F., Salgado, N., Muñoz, P. (2016). Microglia Function in the Normal Brain. In: von Bernhardi, R. (eds) Glial Cells in Health and Disease of the CNS. Advances in Experimental Medicine and Biology, vol 949. Springer, Cham. https://doi.org/10.1007/978-3-319-40764-7_4

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