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Microglia: A Double-Sided Sword in Stroke

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Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

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Abstract

Microglia are the residential immune cells in the central nervous system (CNS). They serve as the first line of defense against CNS injuries such as ischemic stroke. Microglia express a wide range of surface receptors, which control the “On” or “Off” responses of microglia and maintain their functional homeostasis. Upon activation, these highly plastic cells may assume diverse phenotypes and play dualistic roles in brain injury and recovery. In this review, we describe the main surface receptors that involve in microglial activation after stroke, with a focus on their engagement of distinct functional programs. We also discuss the different roles of activated microglia in ischemic brain injury and post-injury brain repair. Further identification of the microglial receptors and/or signaling pathways that are in charge of functional phenotype switch is essential for the research in the stroke field and for the identification of therapeutic targets.

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Abbreviations

CD200R:

CD200 receptor

CNS:

Central nervous system

CX3CR1:

CX3C chemokine receptor 1

DCs:

Dendritic cells

Gals:

Galectins

HMGB1:

High-mobility group box 1

HSP:

Heat shock protein

IFN-γ:

Interferon-gamma

IgSF:

Immunoglobulin superfamily

iNOS:

Inducible nitric oxide synthase

KO:

Knockout

NO:

Nitric oxide

Nox:

NADPH oxidase

NSC:

Neural stem cells

OPC:

Oligodendrocyte progenitor cell

pro-MMP-9:

pro-matrix metalloproteinase-9

RAGE:

Receptor for advanced glycation endproducts

ROS:

Reactive oxygen species

SGZ:

Subgranular zone

SVZ:

Subventricular zone

TGF-β:

Transforming growth factor-β

TIMP-1:

Tissue inhibitor of metalloproteinases-1

TNF-α:

Tumor necrosis factor-α

TREM:

Triggering receptors expressed on myeloid cells

VEGF:

Vascular endothelial growth factor

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Chan WY, Kohsaka S, Rezaie P. The origin and cell lineage of microglia: new concepts. Brain Res Rev. 2007;53(2):344–54.

    Article  CAS  PubMed  Google Scholar 

  3. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol. 2011;11(11):775–87.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, et al. Evidence for synaptic stripping by cortical microglia. Glia. 2007;55(4):360–8.

    Article  PubMed  Google Scholar 

  6. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29(13):3974–80.

    Article  CAS  PubMed  Google Scholar 

  7. Hu X, Liou AK, Leak RK, Xu M, An C, Suenaga J, et al. Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles. Prog Neurobiol. 2014;119–120:60–84.

    Google Scholar 

  8. Wang J, Dore S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain. 2007;130(Pt 6):1643–52. Epub 2007/05/26.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J, et al. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia. 2009;57(8):835–49. Epub 2008/12/05.

    Article  PubMed  Google Scholar 

  10. Kwon MJ, Kim J, Shin H, Jeong SR, Kang YM, Choi JY, et al. Contribution of macrophages to enhanced regenerative capacity of dorsal root Ganglia sensory neurons by conditioning injury. J Neurosci. 2013;33(38):15095–108. Epub 2013/09/21.

    Article  CAS  PubMed  Google Scholar 

  11. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013;16(9):1211–8. Epub 2013/07/23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke. 2007;38(1):146–52.

    Article  CAS  PubMed  Google Scholar 

  14. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol. 2015;11(1):56–64.

    Article  PubMed  Google Scholar 

  15. Ford JW, McVicar DW. TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol. 2009;21(1):38–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol. 2006;177(4):2051–5.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sessa G, Podini P, Mariani M, Meroni A, Spreafico R, Sinigaglia F, et al. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci. 2004;20(10):2617–28.

    Article  PubMed  Google Scholar 

  19. Zhu C, Herrmann US, Li B, Abakumova I, Moos R, Schwarz P, et al. Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains. Neurobiol Aging. 2015;36(5):1994–2003.

    Article  CAS  PubMed  Google Scholar 

  20. Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, et al. Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener. 2014;9:20. Epub 2014/06/05.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J Neurosci. 2015;35(8):3384–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sieber MW, Jaenisch N, Brehm M, Guenther M, Linnartz-Gerlach B, Neumann H, et al. Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke. PLoS One. 2013;8(1), e52982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med. 2015;212(3):287–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem. 2009;109(4):1144–56. Epub 2009/03/24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Panina Bordignon P, et al. The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem. 2009;110(1):284–94.

    Article  CAS  PubMed  Google Scholar 

  26. Matsumoto S, Tanaka J, Yano H, Takahashi H, Sugimoto K, Ohue S, et al. CD200+ and CD200- macrophages accumulated in ischemic lesions of rat brain: the two populations cannot be classified as either M1 or M2 macrophages. J Neuroimmunol. 2015;282:7–20.

    Article  CAS  PubMed  Google Scholar 

  27. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290(5497):1768–71. Epub 2000/12/02.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ, Zhang YJ, et al. CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson’s disease. J Neuroinflammation. 2011;8:154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Takahashi H, Imai Y, et al. Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion. Neurosci Lett. 2007;418(1):44–8. Epub 2007/04/04.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lyons A, Lynch AM, Downer EJ, Hanley R, O’Sullivan JB, Smith A, et al. Fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway attenuates microglial activation in vivo and in vitro. J Neurochem. 2009;110(5):1547–56.

    Article  CAS  PubMed  Google Scholar 

  33. Mattison HA, Nie H, Gao H, Zhou H, Hong JS, Zhang J. Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice. J Neuroimmunol. 2013;257(1-2):110–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tang Z, Gan Y, Liu Q, Yin JX, Liu Q, Shi J, Shi FD. CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinflammation. 2014;11:11–26.

    Article  CAS  Google Scholar 

  35. Pimentel-Coelho PM, Michaud JP, Rivest S. Evidence for a gender-specific protective role of innate immune receptors in a model of perinatal brain injury. J Neurosci. 2013;33(28):11556–72.

    Article  CAS  PubMed  Google Scholar 

  36. Donnelly DJ, Longbrake EE, Shawler TM, Kigerl KA, Lai W, Tovar CA, et al. Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci. 2011;31(27):9910–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J. 2010;24(4):1043–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sparvero LJ, Asafu-Adjei D, Kang R, Tang D, Amin N, Im J, et al. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med. 2009;7:17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Bianchi R, Kastrisianaki E, Giambanco I, Donato R. S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release. J Biol Chem. 2011;286(9):7214–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barateiro A, Afonso V, Santos G, Cerqueira JJ, Brites D, van Horssen J, et al. S100B as a potential biomarker and therapeutic target in multiple sclerosis. Mol Neurobiol. 2015. Epub 2015/07/18.

    Google Scholar 

  41. Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177(5):2549–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Origlia N, Criscuolo C, Arancio O, Yan SS, Domenici L. RAGE inhibition in microglia prevents ischemia-dependent synaptic dysfunction in an amyloid-enriched environment. J Neurosci. 2014;34(26):8749–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Muhammad S, Barakat W, Stoyanov S, Murikinati S, Yang H, Tracey KJ, et al. The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci. 2008;28(46):12023–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liesz A, Dalpke A, Mracsko E, Antoine DJ, Roth S, Zhou W, et al. DAMP signaling is a key pathway inducing immune modulation after brain injury. J Neurosci. 2015;35(2):583–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Rabinovich GA, Toscan MA, Jackson SS, Vasta GR. Functions of cell surface galectin-glycoprotein lattices. Curr Opin Struct Biol. 2007;17(5):513–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vasta GR. Galectins as pattern recognition receptors: structure, function, and evolution. Adv Exp Med Biol. 2012;946:21–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Burguillos MA, Svensson M, Schulte T, Boza-Serrano A, Garcia-Quintanilla A, Kavanagh E, et al. Microglia-secreted Galectin-3 acts as a toll-like receptor 4 ligand and contributes to microglial activation. Cell Rep. 2015. doi:10.1016/j.celrep.2015.02.012.

    Google Scholar 

  48. Young CC, Al-Dalahmah O, Lewis NJ, Brooks KJ, Jenkins MM, Poirier F, et al. Blocked angiogenesis in Galectin-3 null mice does not alter cellular and behavioral recovery after middle cerebral artery occlusion stroke. Neurobiol Dis. 2014;63:155–64.

    Article  CAS  PubMed  Google Scholar 

  49. Rabinovich GA, Croci DO. Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. Immunity. 2012;36(3):322–35.

    Article  CAS  PubMed  Google Scholar 

  50. Wesley UV, Vemuganti R, Ayvaci ER, Dempsey RJ. Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling. Brain Res. 2013;1496:1–9.

    Article  CAS  PubMed  Google Scholar 

  51. Lalancette-Hebert M, Swarup V, Beaulieu JM, Bohacek I, Abdelhamid E, Weng YC, et al. Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. J Neurosci. 2012;32(30):10383–95.

    Article  CAS  PubMed  Google Scholar 

  52. Pasquini LA, Millet V, Hoyos HC, Giannoni JP, Croci DO, Marder M, et al. Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function. Cell Death Differ. 2011;18(11):1746–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999;19(8):819–34.

    Article  CAS  PubMed  Google Scholar 

  54. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391–7.

    Article  CAS  PubMed  Google Scholar 

  55. An C, Shi Y, Li P, Hu X, Gan Y, Stetler RA, et al. Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol. 2014;115:6–24.

    Article  CAS  PubMed  Google Scholar 

  56. Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev. 1996;76(2):319–70.

    CAS  PubMed  Google Scholar 

  57. Jean WC, Spellman SR, Nussbaum ES, Low WC. Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery. 1998;43(6):1382–96; discussion 96–7.

    CAS  PubMed  Google Scholar 

  58. Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH, et al. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci. 2009;29(5):1319–30.

    Article  CAS  PubMed  Google Scholar 

  59. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112–9.

    Article  CAS  PubMed  Google Scholar 

  60. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11(10):700–14.

    Article  CAS  PubMed  Google Scholar 

  61. Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149–60.

    Article  CAS  PubMed  Google Scholar 

  62. Semple BD, Kossmann T, Morganti-Kossmann MC. Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab. 2010;30(3):459–73.

    Article  CAS  PubMed  Google Scholar 

  63. Gliem M, Mausberg AK, Lee JI, Simiantonakis I, van Rooijen N, Hartung HP, et al. Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann Neurol. 2012;71(6):743–52.

    Article  CAS  PubMed  Google Scholar 

  64. Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C. Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab. 2002;22(3):308–17.

    Article  CAS  PubMed  Google Scholar 

  65. Schaller B. Prospects for the future: the role of free radicals in the treatment of stroke. Free Radic Biol Med. 2005;38(4):411–25.

    Article  CAS  PubMed  Google Scholar 

  66. Miller AA, Dusting GJ, Roulston CL, Sobey CG. NADPH-oxidase activity is elevated in penumbral and non-ischemic cerebral arteries following stroke. Brain Res. 2006;1111(1):111–6.

    Article  CAS  PubMed  Google Scholar 

  67. McCann SK, Dusting GJ, Roulston CL. Early increase of Nox4 NADPH oxidase and superoxide generation following endothelin-1-induced stroke in conscious rats. J Neurosci Res. 2008;86(11):2524–34.

    Article  CAS  PubMed  Google Scholar 

  68. Chan EC, Jiang F, Peshavariya HM, Dusting GJ. Regulation of cell proliferation by NADPH oxidase-mediated signaling: potential roles in tissue repair, regenerative medicine and tissue engineering. Pharmacol Ther. 2009;122(2):97–108.

    Article  CAS  PubMed  Google Scholar 

  69. Weston RM, Lin B, Dusting GJ, Roulston CL. Targeting oxidative stress injury after ischemic stroke in conscious rats: limited benefits with apocynin highlight the need to incorporate long term recovery. Stroke Res Treat. 2013;2013:648061.

    PubMed  PubMed Central  Google Scholar 

  70. Iadecola C, Zhang F, Xu X. Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Phys. 1995;268(1 Pt 2):R286–92.

    CAS  Google Scholar 

  71. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Phys. 1996;271(5 Pt 1):C1424–37.

    CAS  Google Scholar 

  72. Horn KP, Busch SA, Hawthorne AL, van Rooijen N, Silver J. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J Neurosci. 2008;28(38):9330–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kitayama M, Ueno M, Itakura T, Yamashita T. Activated microglia inhibit axonal growth through RGMa. PLoS One. 2011;6(9), e25234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ponomarev ED, Veremeyko T, Weiner HL. MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in normal and diseased CNS. Glia. 2013;61(1):91–103.

    Article  PubMed  Google Scholar 

  75. Zhou X, Spittau B, Krieglstein K. TGFbeta signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation. 2012;9:210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ. 1998;5(7):551–62.

    Article  CAS  PubMed  Google Scholar 

  77. Fu R, Shen Q, Xu P, Luo JJ, Tang Y. Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol. 2014;49(3):1422–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Katayama T, Kobayashi H, Okamura T, Yamasaki-Katayama Y, Kibayashi T, Kimura H, et al. Accumulating microglia phagocytose injured neurons in hippocampal slice cultures: involvement of p38 MAP kinase. PLoS One. 2012;7(7), e40813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Young KM, Psachoulia K, Tripathi RB, Dunn SJ, Cossell L, Attwell D, et al. Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron. 2013;77(5):873–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tanaka K, Nogawa S, Suzuki S, Dembo T, Kosakai A. Upregulation of oligodendrocyte progenitor cells associated with restoration of mature oligodendrocytes and myelination in peri-infarct area in the rat brain. Brain Res. 2003;989(2):172–9.

    Article  CAS  PubMed  Google Scholar 

  81. Hsieh J, Aimone JB, Kaspar BK, Kuwabara T, Nakashima K, Gage FH. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J Cell Biol. 2004;164(1):111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ness JK, Wood TL. Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis. Mol Cell Neurosci. 2002;20(3):476–88.

    Article  CAS  PubMed  Google Scholar 

  83. Mason JL, Ye P, Suzuki K, D’Ercole AJ, Matsushima GK. Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci. 2000;20(15):5703–8.

    CAS  PubMed  Google Scholar 

  84. Lalive PH, Paglinawan R, Biollaz G, Kappos EA, Leone DP, Malipiero U, et al. TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. Eur J Immunol. 2005;35(3):727–37.

    Article  CAS  PubMed  Google Scholar 

  85. Filipovic R, Zecevic N. Interaction between microglia and oligodendrocyte cell progenitors involves Golli proteins. Ann N Y Acad Sci. 2005;1048:166–74.

    Article  CAS  PubMed  Google Scholar 

  86. Tanaka T, Murakami K, Bando Y, Yoshida S. Minocycline reduces remyelination by suppressing ciliary neurotrophic factor expression after cuprizone-induced demyelination. J Neurochem. 2013;127(2):259–70.

    Article  CAS  PubMed  Google Scholar 

  87. Vilhardt F. Microglia: phagocyte and glia cell. Int J Biochem Cell Biol. 2005;37(1):17–21.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  89. Cacci E, Claasen JH, Kokaia Z. Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res. 2005;80(6):789–97.

    Article  CAS  PubMed  Google Scholar 

  90. Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Neuron. 2004;41(4):535–47.

    Article  CAS  PubMed  Google Scholar 

  91. Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, Lindvall O. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A. 1997;94(19):10432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kim BJ, Kim MJ, Park JM, Lee SH, Kim YJ, Ryu S, et al. Reduced neurogenesis after suppressed inflammation by minocycline in transient cerebral ischemia in rat. J Neurol Sci. 2009;279(1–2):70–5.

    Article  CAS  PubMed  Google Scholar 

  93. Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall 2nd GP, et al. Microglia instruct subventricular zone neurogenesis. Glia. 2006;54(8):815–25.

    Article  PubMed  Google Scholar 

  94. Liao H, Huang W, Niu R, Sun L, Zhang L. Cross-talk between the epidermal growth factor-like repeats/fibronectin 6-8 repeats domains of Tenascin-R and microglia modulates neural stem/progenitor cell proliferation and differentiation. J Neurosci Res. 2008;86(1):27–34.

    Article  CAS  PubMed  Google Scholar 

  95. Battista D, Ferrari CC, Gage FH, Pitossi FJ. Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus. Eur J Neurosci. 2006;23(1):83–93.

    Article  PubMed  Google Scholar 

  96. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, Fleisch H, et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development. 1994;120(6):1357–72.

    CAS  PubMed  Google Scholar 

  98. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, et al. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med. 2009;206(5):1089–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S. Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci. 2006;47(8):3595–602.

    Article  PubMed  Google Scholar 

  100. Rymo SF, Gerhardt H, Wolfhagen Sand F, Lang R, Uv A, Betsholtz C. A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. PLoS One. 2011;6(1), e15846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Li Y, Liu DX, Li MY, Qin XX, Fang WG, Zhao WD, et al. Ephrin-A3 and ephrin-A4 contribute to microglia-induced angiogenesis in brain endothelial cells. Anat Rec. 2014;297(10):1908–18.

    Article  CAS  Google Scholar 

  102. Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120(3):613–25. Epub 2012/05/12.

    Article  CAS  PubMed  Google Scholar 

  103. Medina RJ, O’Neill CL, O’Doherty TM, Knott H, Guduric-Fuchs J, Gardiner TA, et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol Med. 2011;17(9–10):1045–55. Epub 2011/06/15.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Zajac E, Schweighofer B, Kupriyanova TA, Juncker-Jensen A, Minder P, Quigley JP, et al. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood. 2013;122(25):4054–67. Epub 2013/11/01.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sugimoto K, Nishioka R, Ikeda A, Mise A, Takahashi H, Yano H, et al. Activated microglia in a rat stroke model express NG2 proteoglycan in peri-infarct tissue through the involvement of TGF-beta1. Glia. 2014;62(2):185–98.

    Article  PubMed  Google Scholar 

  106. Febinger HY, Thomasy HE, Pavlova MN, Ringgold KM, Barf PR, George AM, et al. Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury. J Neuroinflammation. 2015;12:154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Liu Y, Wu XM, Luo QQ, Huang S, Yang QW, Wang FX, et al. CX3CL1/CX3CR1-mediated microglia activation plays a detrimental role in ischemic mice brain via p38MAPK/PKC pathway. J Cereb Blood Flow Metab. 2015;35(10):1623–31.

    CAS  PubMed  Google Scholar 

  108. Wu XM, Liu Y, Qian ZM, Luo QQ, Ke Y. CX3CL1/CX3CR1 Axis plays a key role in ischemia-induced oligodendrocyte injury via p38MAPK signaling pathway. Mol Neurobiol. 2015.

    Google Scholar 

  109. Walter HL, van der Maten G, Antunes AR, Wieloch T, Ruscher K. Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke. J Neuroinflammation. 2015;12:24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. McGuckin CP, Jurga M, Miller AM, Sarnowska A, Wiedner M, Boyle NT, et al. Ischemic brain injury: a consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction. Arch Biochem Biophys. 2013;534(1–2):88–97.

    Article  CAS  PubMed  Google Scholar 

  111. Dentesano G, Serratosa J, Tusell JM, Ramon P, Valente T, Saura J, et al. CD200R1 and CD200 expression are regulated by PPAR-gamma in activated glial cells. Glia. 2014;62(6):982–98. Epub 2014/03/19.

    Article  PubMed  Google Scholar 

  112. Lee JC, Cho JH, Cho GS, Ahn JH, Park JH, Kim IH, et al. Effect of transient cerebral ischemia on the expression of receptor for advanced glycation end products (RAGE) in the gerbil hippocampus proper. Neurochem Res. 2014;39(8):1553–63.

    Article  CAS  PubMed  Google Scholar 

  113. Lok KZ, Basta M, Manzanero S, Arumugam TV. Intravenous immunoglobulin (IVIg) dampens neuronal toll-like receptor-mediated responses in ischemia. J Neuroinflammation. 2015;12:73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Park H, Ku SH, Park H, Hong J, Kim D, Choi BR, et al. RAGE siRNA-mediated gene silencing provides cardioprotection against ventricular arrhythmias in acute ischemia and reperfusion. J Control Release. 2015;217:315–26.

    Article  CAS  PubMed  Google Scholar 

  115. Pimentel-Coelho PM, Michaud JP, Rivest S. C-C chemokine receptor type 2 (CCR2) signaling protects neonatal male mice with hypoxic-ischemic hippocampal damage from developing spatial learning deficits. Behav Brain Res. 2015;286:146–51.

    Article  CAS  PubMed  Google Scholar 

  116. Arakelyan A, Zakharyan R, Hambardzumyan M, Petrkova J, Olsson MC, Petrek M, et al. Functional genetic polymorphisms of monocyte chemoattractant protein 1 and C-C chemokine receptor type 2 in ischemic stroke. J Interf Cytokine Res. 2014;34(2):100–5. Epub 2013/10/03.

    Article  CAS  Google Scholar 

  117. Chu HX, Broughton BR, Kim HA, Lee S, Drummond GR, Sobey CG. Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization. Stroke. 2015;46(7):1929–37. Epub 2015/05/23.

    Article  CAS  PubMed  Google Scholar 

  118. Hammond MD, Taylor RA, Mullen MT, Ai Y, Aguila HL, Mack M, et al. CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci. 2014;34(11):3901–9. Epub 2014/03/14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Wacker BK, Perfater JL, Gidday JM. Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway. J Neurochem. 2012;123(6):954–62. Epub 2012/10/10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tokami H, Ago T, Sugimori H, Kuroda J, Awano H, Suzuki K, Kiyohara Y, Kamouchi M, Kitazono T, REBIOS Investigators. RANTES has a potential to play a neuroprotective role in an autocrine/paracrine manner after ischemic stroke. Brain Res. 2013;1517:122–32.

    Article  CAS  PubMed  Google Scholar 

  121. Dziennis S, Mader S, Akiyoshi K, Ren X, Ayala P, Burrows GG, et al. Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. Metab Brain Dis. 2011;26(2):123–33. Epub 2011/04/08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sorce S, Bonnefont J, Julien S, Marq-Lin N, Rodriguez I, Dubois-Dauphin M, et al. Increased brain damage after ischaemic stroke in mice lacking the chemokine receptor CCR5. Br J Pharmacol. 2010;160(2):311–21. Epub 2010/04/29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tokami H, Ago T, Sugimori H, Kuroda J, Awano H, Suzuki K, et al. RANTES has a potential to play a neuroprotective role in an autocrine/paracrine manner after ischemic stroke. Brain Res. 2013;1517:122–32. Epub 2013/04/23.

    Article  CAS  PubMed  Google Scholar 

  124. Fronz U, Deten A, Baumann F, Kranz A, Weidlich S, Hartig W, et al. Continuous adenosine A2A receptor antagonism after focal cerebral ischemia in spontaneously hypertensive rats. Naunyn Schmiedeberg's Arch Pharmacol. 2014;387(2):165–73. Epub 2013/10/31.

    Article  CAS  Google Scholar 

  125. Melani A, Corti F, Cellai L, Vannucchi MG, Pedata F. Low doses of the selective adenosine A2A receptor agonist CGS21680 are protective in a rat model of transient cerebral ischemia. Brain Res. 2014;1551:59–72. Epub 2014/01/25.

    Article  CAS  PubMed  Google Scholar 

  126. Melani A, Dettori I, Corti F, Cellai L, Pedata F. Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia. Neurol Sci. 2015;36(8):1441–8. Epub 2015/03/26.

    Article  PubMed  Google Scholar 

  127. Choi IY, Lee JC, Ju C, Hwang S, Cho GS, Lee HW, Choi WJ, Jeong LS, Kim WK. A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol. 2011;179:2042–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ryu S, Kwon J, Park H, Choi IY, Hwang S, Gajulapati V, et al. Amelioration of cerebral ischemic injury by a synthetic seco-nucleoside LMT497. Exp Neurol. 2015;24(1):31–40. Epub 2015/03/21.

    Google Scholar 

  129. Li F, Wang L, Li JW, Gong M, He L, Feng R, Dai Z, Li SQ. Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4. BMC Neurosci. 2011;12:111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cheng RD, Ren JJ, Zhang YY, Ye XM. P2X4 receptors expressed on microglial cells in post-ischemic inflammation of brain ischemic injury. Neurochem Int. 2014;67:9–13. Epub 2014/02/04.

    Article  CAS  PubMed  Google Scholar 

  131. Mahi N, Kumar A, Jaggi AS, Singh N, Dhawan R. Possible role of pannexin 1/P2x7 purinoceptor in neuroprotective mechanism of ischemic postconditioning in mice. J Surg Res. 2015;196:190–9.

    Article  CAS  PubMed  Google Scholar 

  132. Bindra CS, Jaggi AS, Singh N. Role of P2X7 purinoceptors in neuroprotective mechanism of ischemic postconditioning in mice. Mol Cell Biochem. 2014;390(1–2):161–73. Epub 2014/02/05.

    Article  CAS  PubMed  Google Scholar 

  133. Cisneros-Mejorado A, Gottlieb M, Cavaliere F, Magnus T, Koch-Nolte F, Scemes E, et al. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage. J Cereb Blood Flow Metab. 2015;35(5):843–50. Epub 2015/01/22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ma XJ, Cheng JW, Zhang J, Liu AJ, Liu W, Guo W, Shen FM, Lu GC. E-selectin deficiency attenuates brain ischemia in mice. CNS Neurosci Ther. 2012;13:903–8.

    Article  CAS  Google Scholar 

  135. Das S, Roy S, Kaul S, Jyothy A, Munshi A. E-selectin gene (S128R) polymorphism in hemorrhagic stroke: Comparison with ischemic stroke. Neurosci Lett. 2014;581:125–8.

    Article  CAS  PubMed  Google Scholar 

  136. Anuncibay-Soto B, Perez-Rodriguez D, Llorente IL, Regueiro-Purrinos M, Gonzalo-Orden JM, Fernandez-Lopez A. Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model. Age (Dordr). 2014;36(5):9703. Epub 2014/09/04.

    Article  CAS  Google Scholar 

  137. Bell MT, Puskas F, Agoston VA, Cleveland Jr JC, Freeman KA, Gamboni F, et al. Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury. Circulation. 2013;128(11 Suppl 1):S152–6.

    Article  CAS  PubMed  Google Scholar 

  138. Woo MS, Wang X, Faustino JV, Derugin N, Wendland MF, Zhou P, et al. Genetic deletion of CD36 enhances injury after acute neonatal stroke. Ann Neurol. 2012;72(6):961–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Li F, Faustino J, Woo MS, Derugin N, Vexler ZS. Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke. J Neurochem. 2015;135(3):445–52.

    Article  CAS  PubMed  Google Scholar 

  140. Kim E, Febbraio M, Bao Y, Tolhurst AT, Epstein JM, Cho S. CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia. Ann Neurol. 2012;71(6):753–64. Epub 2012/06/22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cheyuo C, Aziz M, Yang WL, Jacob A, Zhou M, Wang P. Milk fat globule-EGF factor VIII attenuates CNS injury by promoting neural stem cell proliferation and migration after cerebral ischemia. PLoS One. 2015;10(4), e0122833. Epub 2015/04/14.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Cheyuo C, Jacob A, Wu R, Zhou M, Qi L, Dong W, et al. Recombinant human MFG-E8 attenuates cerebral ischemic injury: its role in anti-inflammation and anti-apoptosis. Neuropharmacology. 2012;62(2):890–900. Epub 2011/10/04.

    Article  CAS  PubMed  Google Scholar 

  143. Neher JJ, Emmrich JV, Fricker M, Mander PK, Thery C, Brown GC. Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci U S A. 2013;110(43):E4098–107. Epub 2013/10/09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Sources of Funding

X Hu is supported by a NIH/National Institute of neurological disorders and stroke (NINDS) grant (NS092618) and a grant from the American Heart Association (13SDG14570025); J Chen is supported by the NIH/NINDS grants (NS095671 and NS089534) and a VA research career scientist award; Y Gao is supported by the Chinese Natural Science Foundation grants (81171149 and 81371306).

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Authors and Affiliations

  1. State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China

    Hong Shi, Mingyue Xu & Yanqin Gao

  2. Department of Anesthesiology of Shanghai Pulmonary Hospital, Tongji University, Shanghai, China

    Hong Shi

  3. Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Mingyue Xu, Yejie Shi & Yanqin Gao

  4. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Jun Chen & Xiaoming Hu

  5. Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA

    Jun Chen & Xiaoming Hu

  6. State Key laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Jun Chen & Xiaoming Hu

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  1. Hong Shi
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  3. Yejie Shi
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  5. Jun Chen
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Correspondence to Xiaoming Hu .

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Editors and Affiliations

  1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Jun Chen

  2. Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    John H. Zhang

  3. Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, California, USA

    Xiaoming Hu

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Shi, H., Xu, M., Shi, Y., Gao, Y., Chen, J., Hu, X. (2016). Microglia: A Double-Sided Sword in Stroke. In: Chen, J., Zhang, J., Hu, X. (eds) Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-32337-4_7

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