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Dual Functions of Microglia in Ischemic Stroke

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Abstract

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However, increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes, and endothelial cells within the brain parenchyma and the neurovascular unit.

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References

  1. Gulke E, Gelderblom M, Magnus T. Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Disord 2018, 11: 1756286418774254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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: 56–64.

    Article  PubMed  Google Scholar 

  3. Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Prog Neurobiol 2017, 157: 247–272.

    Article  CAS  PubMed  Google Scholar 

  4. Wen YD, Zhang HL, Qin ZH. Inflammatory mechanism in ischemic neuronal injury. Neurosci Bull 2006, 22: 171–182.

    CAS  PubMed  Google Scholar 

  5. Chen G, Luo X, Qadri MY, Berta T, Ji RR. Sex-dependent glial signaling in pathological pain: distinct roles of spinal microglia and astrocytes. Neurosci Bull 2018, 34: 98–108.

    Article  CAS  PubMed  Google Scholar 

  6. Fang X, Sun D, Wang Z, Yu Z, Liu W, Pu Y, et al. MiR-30a positively regulates the inflammatory response of microglia in experimental autoimmune encephalomyelitis. Neurosci Bull 2017, 33: 603–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fumagalli M, Lombardi M, Gressens P, Verderio C. How to reprogram microglia toward beneficial functions. Glia 2018.

  8. Wang J, Xing H, Wan L, Jiang X, Wang C, Wu Y. Treatment targets for M2 microglia polarization in ischemic stroke. Biomed Pharmacother 2018, 105: 518–525.

    Article  CAS  PubMed  Google Scholar 

  9. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Ann Rev Immunol 2009, 27: 119–145.

    Article  CAS  PubMed  Google Scholar 

  10. Chamorro A, Hallenbeck J. The harms and benefits of inflammatory and immune responses in vascular disease. Stroke 2006, 37: 291–293.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. Febs Journal 2009, 276: 13–26.

    Article  CAS  PubMed  Google Scholar 

  12. Yenari MA, Kauppinen TM, Swanson RA. Microglial activation in stroke: therapeutic targets. Neurotherapeutics 2010, 7: 378–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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: 91–103.

    Article  PubMed  Google Scholar 

  14. Al Mamun A, Chauhan A, Yu H, Xu Y, Sharmeen R, Liu F. Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice. Eur J Neurosci 2018, 47: 140–149.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chhor V, Le Charpentier T, Lebon S, Ore MV, Celador IL, Josserand J, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav Immun 2013, 32: 70–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gulyas B, Toth M, Schain M, Airaksinen A, Vas A, Kostulas K, et al. Evolution of microglial activation in ischaemic core and pen-infarct regions after stroke: A PET study with the TSPO molecular imaging biomarker C-11 vinpocetine. J Neurol Sci 2012, 320: 110–117.

    Article  CAS  PubMed  Google Scholar 

  18. Morrison HW, Filosa JA. A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 2013, 10.

  19. Yan T, Chopp M, Chen J. Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke. Neurosci Bull 2015, 31: 717–734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eyo UB, Gu N, De S, Dong H, Richardson JR, Wu LJ. Modulation of microglial process convergence toward neuronal dendrites by extracellular calcium. J Neurosci 2015, 35: 2417–2422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu LJ. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci 2014, 34: 10528–10540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rupalla K, Allegrini PR, Sauer D, Wiessner C. Time course of microglia activation and apoptosis in various brain regions after permanent focal cerebral ischemia in mice. Acta Neuropathol 1998, 96: 172–178.

    Article  CAS  PubMed  Google Scholar 

  23. Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 2001, 32: 1208–1215.

    Article  CAS  PubMed  Google Scholar 

  24. Gorlamandala N, Parmar J, Craig AJ, Power JM, Moorhouse AJ, Krishnan AV, et al. Focal ischaemic infarcts expand faster in cerebellar cortex than cerebral cortex in a mouse photothrombotic stroke model. Transl Stroke Res 2018, 9: 643–653.

    Article  PubMed  Google Scholar 

  25. 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: E4098–E4107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shi QJ, Wang H, Liu ZX, Fang SH, Song XM, Lu YB, et al. HAMI 3379, a CysLT2R antagonist, dose- and time-dependently attenuates brain injury and inhibits microglial inflammation after focal cerebral ischemia in rats. Neuroscience 2015, 291: 53–69.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Z, Chopp M, Powers C. Temporal profile of microglial response following transient (2h) middle cerebral artery occlusion. Brain Research 1997, 744: 189–198.

    Article  CAS  PubMed  Google Scholar 

  28. Perego C, Fumagalli S, De Simoni MG. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 2011, 8: 174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nowicka D, Rogozinska K, Aleksy M, Witte OW, Skangiel-Kramska J. Spatiotemporal dynamics of astroglial and microglial responses after photothrombotic stroke in the rat brain. Acta Neurobiol Exp (Wars) 2008, 68: 155–168.

    Google Scholar 

  30. Ladwig A, Walter HL, Hucklenbroich J, Willuweit A, Langen KJ, Fink GR, et al. Osteopontin augments M2 microglia response and separates M1- and M2-polarized microglial activation in permanent focal cerebral ischemia. Mediators Inflamm 2017, 2017: 7189421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Qin C, Fan WH, Liu Q, Shang K, Murugan M, Wu LJ, et al. Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway. Stroke 2017, 48: 3336–3346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang J, Xie Y, Sun X, Zeh HJ, III, Kang R, Lotze MT, et al. DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’. Ageing Res Rev 2015, 24: 3–16.

    Article  CAS  Google Scholar 

  33. Fang H, Wang PF, Zhou Y, Wang YC, Yang QW. Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. J Neuroinflammation 2013, 10: 27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol 2016, 142: 23–44.

    Article  CAS  PubMed  Google Scholar 

  35. Zhao SC, Ma LS, Chu ZH, Xu H, Wu WQ, Liu F. Regulation of microglial activation in stroke. Acta Pharmacol Sin 2017, 38: 445–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ji Y, Zhou Y, Pan J, Li X, Wang H, Wang Y. Temporal pattern of Toll-like receptor 9 upregulation in neurons and glial cells following cerebral ischemia reperfusion in mice. Int J Neurosci 2016, 126: 269–277.

    Article  CAS  PubMed  Google Scholar 

  37. Bohacek I, Cordeau P, Lalancette-Hebert M, Gorup D, Weng YC, Gajovic S, et al. Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury. J Neuroinflammation 2012, 9: 17.

    Article  CAS  Google Scholar 

  38. Ando K, Kanazawa S, Tetsuka T, Ohta S, Jiang X, Tada T, et al. Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene 2003, 22: 7796–7803.

    Article  CAS  PubMed  Google Scholar 

  39. Wei Z, Chigurupati S, Arumugam TV, Jo DG, Li H, Chan SL. Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia. Stroke 2011, 42: 2589–2594.

    Article  CAS  PubMed  Google Scholar 

  40. Yuan Y, Rangarajan P, Kan EM, Wu Y, Wu C, Ling EA. Scutellarin regulates the Notch pathway and affects the migration and morphological transformation of activated microglia in experimentally induced cerebral ischemia in rats and in activated BV-2 microglia. J Neuroinflammation 2015, 12.

  41. Arumugam TV, Chan SL, Jo DG, Yilmaz G, Tang SC, Cheng AW, et al. Gamma secretase-mediated notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med 2006, 12: 621–623.

    Article  CAS  PubMed  Google Scholar 

  42. Yao L, Kan EM, Kaur C, Dheen ST, Hao A, Lu J, et al. Notch-1 signaling regulates microglia activation via NF-kappa B pathway after hypoxic exposure in vivo and in vitro. PLoS One 2013, 8.

  43. Wu LJ, Wu G, Akhavan Sharif MR, Baker A, Jia Y, Fahey FH, et al. The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke. Nat Neurosci 2012, 15: 565–573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu LJ. Voltage-gated proton channel HV1 in microglia. Neuroscientist 2014, 20: 599–609.

    Article  CAS  PubMed  Google Scholar 

  45. Song S, Wang S, Pigott VM, Jiang T, Foley LM, Mishra A, et al. Selective role of Na(+) /H(+) exchanger in Cx3cr1(+) microglial activation, white matter demyelination, and post-stroke function recovery. Glia 2018, 66: 2279–2298.

    Article  PubMed  Google Scholar 

  46. Yu Y, Li J, Zhou H, Xiong Y, Wen Y, Li H. Functional importance of the TGF-beta1/Smad3 signaling pathway in oxygen-glucose-deprived (OGD) microglia and rats with cerebral ischemia. Int J Biol Macromol 2018, 116: 537–544.

    Article  CAS  PubMed  Google Scholar 

  47. Li D, Lang W, Zhou C, Wu C, Zhang F, Liu Q, et al. Upregulation of microglial ZEB1 ameliorates brain damage after acute ischemic stroke. Cell Rep 2018, 22: 3574–3586.

    Article  CAS  PubMed  Google Scholar 

  48. Chen S, Dong Z, Cheng M, Zhao Y, Wang M, Sai N, et al. Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke. J Neuroinflammation 2017, 14: 187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liang K, Zhu L, Tan J, Shi W, He Q, Yu B. Identification of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression. Neurosci Bull 2015, 31: 480–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cruz SA, Hari A, Qin Z, Couture P, Huang H, Lagace DC, et al. Loss of IRF2BP2 in microglia increases inflammation and functional deficits after focal ischemic brain injury. Front Cell Neurosci 2017, 11: 201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang M, Wu X, Xu Y, He M, Yang J, Li J, et al. The cystathionine beta-synthase/hydrogen sulfide pathway contributes to microglia-mediated neuroinflammation following cerebral ischemia. Brain Behav Immun 2017, 66: 332–346.

    Article  CAS  PubMed  Google Scholar 

  52. Li Y, Xu L, Zeng K, Xu Z, Suo D, Peng L, et al. Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARalpha/gamma dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses. Brain Behav Immun 2017, 66: 289–301.

    Article  CAS  PubMed  Google Scholar 

  53. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008, 57: 178–201.

    Article  CAS  PubMed  Google Scholar 

  54. del Zoppo GJ. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience 2009, 158: 972–982.

    Article  CAS  PubMed  Google Scholar 

  55. Pan W, Kastin AJ. Tumor necrosis factor and stroke: Role of the blood-brain barrier. Prog Neurobiol 2007, 83: 363–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jolivel V, Bicker F, Binamé F, Ploen R, Keller S, Gollan R, et al. Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol 2015, 129: 279–295.

    Article  PubMed  Google Scholar 

  57. Welser JV, Li L, Milner R. Microglial activation state exerts a biphasic influence on brain endothelial cell proliferation by regulating the balance of TNF and TGF-beta1. J Neuroinflammation 2010, 7: 89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008, 132: 645–660.

    Article  CAS  PubMed  Google Scholar 

  59. Tsai YW, Yang YR, Wang PS, Wang RY. Intermittent hypoxia after transient focal ischemia induces hippocampal neurogenesis and c-Fos expression and reverses spatial memory deficits in rats. PLoS One 2011, 6: 9.

    Google Scholar 

  60. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002, 8: 963–970.

    Article  CAS  PubMed  Google Scholar 

  61. Tonchev AB. Brain ischemia, neurogenesis, and neurotrophic receptor expression in primates. Archives Italiennes De Biologie 2011, 149: 225–231.

    PubMed  Google Scholar 

  62. 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: 835–849.

    Article  PubMed  Google Scholar 

  63. Heldmann U, Mine Y, Kokaia Z, Ekdahl CT, Lindvall O. Selective depletion of Mac-1-expressing microglia in rat subventricular zone does not alter neurogenic response early after stroke. Exp Neurol 2011, 229: 391–398.

    Article  CAS  PubMed  Google Scholar 

  64. Choi JY, Kim JY, Kim JY, Park J, Lee WT, Lee JE. M2 Phenotype microglia-derived cytokine stimulates proliferation and neuronal differentiation of endogenous stem cells in ischemic brain. Exp Neurobiol 2017, 26: 33–41.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhao X, Eyo UB, Murugan M, Wu LJ. Microglial interactions with the neurovascular system in physiology and pathology. Dev Neurobiol 2018, 78: 604–617.

    Article  PubMed  PubMed Central  Google Scholar 

  66. 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: 1089–1102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang ZG, Zhang L, Jiang Q, Zhang RL, Davies K, Powers C, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 2000, 106: 829–838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xie L, Mao X, Jin K, Greenberg DA. Vascular endothelial growth factor-B expression in postischemic rat brain. Vasc Cell 2013, 5: 8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nie J, Yang X. Modulation of synaptic plasticity by exercise training as a basis for ischemic stroke rehabilitation. Cell Mol Neurobiol 2017, 37: 5–16.

    Article  CAS  PubMed  Google Scholar 

  70. Huerta PT, Volpe BT. Transcranial magnetic stimulation, synaptic plasticity and network oscillations. J Neuroeng Rehabil 2009, 6: 7.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lauro C, Catalano M, Trettel F, Limatola C, Sci NYA. Fractalkine in the nervous system: neuroprotective or neurotoxic molecule? Neuroimmunomodulation Health Dis 2015, 1351: 141–148.

    CAS  Google Scholar 

  72. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 2015, 36: 605–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, 3rd, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013, 155: 1596–1609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Miyamoto A, Wake H, Ishikawa AW, Eto K, Shibata K, Murakoshi H, et al. Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun 2016, 7: 12540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang J, Malik A, Choi HB, Ko RWY, Dissing-Olesen L, MacVicar BA. Microglial CR3 Activation Triggers Long-Term Synaptic Depression in the Hippocampus via NADPH Oxidase. Neuron 2014, 82: 195–207.

    Article  CAS  PubMed  Google Scholar 

  76. Maki T, Hayakawa K, Pham LD, Xing C, Lo EH, Arai K. Biphasic mechanisms of neurovascular unit injury and protection in CNS diseases. CNS Neurol Disord Drug Targets 2013, 12: 302–315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tian DS, Li CY, Qin C, Murugan M, Wu LJ, Liu JL. Deficiency in the voltage-gated proton channel Hv1 increases M2 polarization of microglia and attenuates brain damage from photothrombotic ischemic stroke. J Neurochem 2016, 139: 96–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tikamdas R, Singhal S, Zhang P, Smith JA, Krause EG, Stevens SM, Jr., et al. Ischemia-responsive protein 94 is a key mediator of ischemic neuronal injury-induced microglial activation. J Neurochem 2017, 142: 908–919.

    Article  CAS  PubMed  Google Scholar 

  79. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 2007, 27: 2596–2605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu LJ. Microglial voltage-gated proton channel Hv1 in ischemic stroke. Transl Stroke Res 2014, 5: 99–108.

    Article  CAS  PubMed  Google Scholar 

  81. Liu J, Tian D, Murugan M, Eyo UB, Dreyfus CF, Wang W, et al. Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage. J Neurochem 2015, 135: 347–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Moss DW, Bates TE. Activation of murine microglial cell lines by lipopolysaccharide and interferon-gamma causes NO-mediated decreases in mitochondrial and cellular function. Eur J Neurosci 2001, 13: 529–538.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  84. Eyo UB, Bispo A, Liu J, Sabu S, Wu R, DiBona VL, et al. The GluN2A subunit regulates neuronal NMDA receptor-induced microglia-neuron physical interactions. Sci Rep 2018, 8: 828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, et al. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 2006, 281: 21362–21368.

    Article  CAS  PubMed  Google Scholar 

  86. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006, 9: 917–924.

    Article  CAS  PubMed  Google Scholar 

  87. Mizuno T, Kawanokuchi J, Numata K, Suzumura A. Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 2003, 979: 65–70.

    Article  CAS  PubMed  Google Scholar 

  88. Liang KJ, Lee JE, Wang YD, Ma W, Fontainhas AM, Fariss RN, et al. Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. Invest Ophthalmol Vis Sci 2009, 50: 4444–4451.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ. Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. J Cereb Blood Flow Metab 2008, 28: 1707–1721.

    Article  CAS  PubMed  Google Scholar 

  91. Fumagalli S, Perego C, Ortolano F, De Simoni MG. CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. Glia 2013, 61: 827–842.

    Article  PubMed  Google Scholar 

  92. Noda M, Doi Y, Liang J, Kawanokuchi J, Sonobe Y, Takeuchi H, et al. Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem 2016, 291: 14388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee S, Lee J, Kim S, Park JY, Lee WH, Mori K, et al. A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. J Immunol 2007, 179: 3231–3241.

    Article  CAS  PubMed  Google Scholar 

  94. Xing C, Wang X, Cheng C, Montaner J, Mandeville E, Leung W, et al. Neuronal production of lipocalin-2 as a help-me signal for glial activation. Stroke 2014, 45: 2085–2092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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: 647–657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wu R, Li X, Xu P, Huang L, Cheng J, Huang X, et al. TREM2 protects against cerebral ischemia/reperfusion injury. Mol Brain 2017, 10: 20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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: 3384–3396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu W, Tang Y, Feng J. Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 2011, 89: 141–146.

    Article  CAS  PubMed  Google Scholar 

  99. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 2009, 137: 47–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract 2010, 10: 167–184.

    Article  PubMed  Google Scholar 

  101. Griffin WS. Inflammation and neurodegenerative diseases. Am J Clin Nutr 2006, 83: 470S–474S.

    Article  CAS  PubMed  Google Scholar 

  102. John GR, Chen L, Rivieccio MA, Melendez-Vasquez CV, Hartley A, Brosnan CF. Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis. J Neurosci 2004, 24: 2837–2845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Herx LM, Rivest S, Yong VW. Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol 2000, 165: 2232–2239.

    Article  CAS  PubMed  Google Scholar 

  104. Chao CC, Hu S, Sheng WS, Bu D, Bukrinsky MI, Peterson PK. Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism. Glia 1996, 16: 276–284.

    Article  CAS  PubMed  Google Scholar 

  105. Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC. Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 2000, 7: 153–159.

    Article  CAS  PubMed  Google Scholar 

  106. Schipke CG, Boucsein C, Ohlemeyer C, Kirchhoff F, Kettenmann H. Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. Faseb J 2002, 16: 255–257.

    Article  CAS  PubMed  Google Scholar 

  107. Lehrmann E, Christensen T, Zimmer J, Diemer NH, Finsen B. Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occlusion. J Comp Neurol 1997, 386: 461–476.

    Article  CAS  PubMed  Google Scholar 

  108. Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia 2005, 50: 281–286.

    Article  PubMed  Google Scholar 

  109. Xie M, Yi C, Luo X, Xu S, Yu Z, Tang Y, et al. Glial gap junctional communication involvement in hippocampal damage after middle cerebral artery occlusion. Ann Neurol 2011, 70: 121–132.

    Article  PubMed  Google Scholar 

  110. Zanotti S, Charles A. Extracellular calcium sensing by glial cells: low extracellular calcium induces intracellular calcium release and intercellular signaling. J Neurochem 1997, 69: 594–602.

    Article  CAS  PubMed  Google Scholar 

  111. Shigemoto-Mogami Y, Koizumi S, Tsuda M, Ohsawa K, Kohsaka S, Inoue K. Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5. J Neurochem 2001, 78: 1339–1349.

    Article  CAS  PubMed  Google Scholar 

  112. Lu YL, Wang R, Huang HT, Qin HM, Liu CH, Xiang Y, et al. Association of S100B polymorphisms and serum S100B with risk of ischemic stroke in a Chinese population. Sci Rep 2018, 8: 971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Edwards MM, Robinson SR. TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease. J Neural Transm (Vienna) 2006, 113: 1709–1715.

    Article  CAS  Google Scholar 

  114. Reali C, Scintu F, Pillai R, Donato R, Michetti F, Sogos V. S100b counteracts effects of the neurotoxicant trimethyltin on astrocytes and microglia. J Neurosci Res 2005, 81: 677–686.

    Article  CAS  PubMed  Google Scholar 

  115. Tramontina F, Tramontina AC, Souza DF, Leite MC, Gottfried C, Souza DO, et al. Glutamate uptake is stimulated by extracellular S100B in hippocampal astrocytes. Cell Mol Neurobiol 2006, 26: 81–86.

    PubMed  Google Scholar 

  116. Blais V, Rivest S. Effects of TNF-alpha and IFN-gamma on nitric oxide-induced neurotoxicity in the mouse brain. J Immunol 2004, 172: 7043–7052.

    Article  CAS  PubMed  Google Scholar 

  117. Matute C, Domercq M, Perez-Samartin A, Ransom BR. Protecting white matter from stroke injury. Stroke 2013, 44: 1204–1211.

    Article  PubMed  Google Scholar 

  118. Miller BA, Crum JM, Tovar CA, Ferguson AR, Bresnahan JC, Beattie MS. Developmental stage of oligodendrocytes determines their response to activated microglia in vitro. J Neuroinflammation 2007, 4: 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zajicek JP, Wing M, Scolding NJ, Compston DA. Interactions between oligodendrocytes and microglia. A major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain 1992, 115 (Pt 6): 1611–1631.

  120. Kaur C, Ling EA. Periventricular white matter damage in the hypoxic neonatal brain: role of microglial cells. Prog Neurobiol 2009, 87: 264–280.

    Article  CAS  PubMed  Google Scholar 

  121. Yang Y, Jalal FY, Thompson JF, Walker EJ, Candelario-Jalil E, Li L, et al. Tissue inhibitor of metalloproteinases-3 mediates the death of immature oligodendrocytes via TNF-alpha/TACE in focal cerebral ischemia in mice. J Neuroinflammation 2011, 8: 108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. O’Kusky J, Ye P. Neurodevelopmental effects of insulin-like growth factor signaling. Front Neuroendocrinol 2012, 33: 230–251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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: 149–160.

    Article  CAS  PubMed  Google Scholar 

  125. van der Goes A, Brouwer J, Hoekstra K, Roos D, van den Berg TK, Dijkstra CD. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol 1998, 92: 67–75.

    Article  PubMed  Google Scholar 

  126. Haynes RL, Baud O, Li J, Kinney HC, Volpe JJ, Folkerth DR. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol 2005, 15: 225–233.

    Article  CAS  PubMed  Google Scholar 

  127. Uchida H, Fujita Y, Matsueda M, Umeda M, Matsuda S, Kato H, et al. Damage to neurons and oligodendrocytes in the hippocampal CA1 sector after transient focal ischemia in rats. Cell Mol Neurobiol 2010, 30: 1125–1134.

    Article  CAS  PubMed  Google Scholar 

  128. Merrill JE, Ignarro LJ, Sherman MP, Melinek J, Lane TE. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol 1993, 151: 2132–2141.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  130. Jolivel V, Bicker F, Biname F, Ploen R, Keller S, Gollan R, et al. Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol 2015, 129: 279–295.

    Article  PubMed  Google Scholar 

  131. Lou N, Takano T, Pei Y, Xavier AL, Goldman SA, Nedergaard M. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proc Natl Acad Sci U S A 2016, 113: 1074–1079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 2000, 106: 829–838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res 1999, 85: 753–766.

    Article  CAS  PubMed  Google Scholar 

  134. Hayashi T, Noshita N, Sugawara T, Chan PH. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 2003, 23: 166–180.

    Article  CAS  PubMed  Google Scholar 

  135. Kuo NT, Benhayon D, Przybylski RJ, Martin RJ, LaManna JC. Prolonged hypoxia increases vascular endothelial growth factor mRNA and protein in adult mouse brain. J Appl Physiol (1985) 1999, 86: 260–264.

    Google Scholar 

  136. 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 (Hoboken) 2014, 297: 1908–1918.

    Article  CAS  Google Scholar 

  137. Kanazawa M, Miura M, Toriyabe M, Koyama M, Hatakeyama M, Ishikawa M, et al. Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats. Sci Rep 2017, 7: 42582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jiang M, Liu X, Zhang D, Wang Y, Hu X, Xu F, et al. Celastrol treatment protects against acute ischemic stroke-induced brain injury by promoting an IL-33/ST2 axis-mediated microglia/macrophage M2 polarization. J Neuroinflammation 2018, 15: 78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. He Y, Ma X, Li D, Hao J. Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-kappaB p65 signaling. J Cereb Blood Flow Metab 2017, 37: 2938–2951.

    Article  CAS  PubMed  Google Scholar 

  140. Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 2013, 4: e525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yang Y, Salayandia VM, Thompson JF, Yang LY, Estrada EY, Yang Y. Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery. J Neuroinflammation 2015, 12: 26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Pepe G, Calderazzi G, De Maglie M, Villa AM, Vegeto E. Heterogeneous induction of microglia M2a phenotype by central administration of interleukin-4. J Neuroinflammation 2014, 11: 211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Xia CY, Zhang S, Gao Y, Wang ZZ, Chen NH. Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int Immunopharmacol 2015, 25: 377–382.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  145. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci 2011, 31: 16064–16069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This review was supported by the National Natural Science Foundation of China (81571132, 81873743, and 81801223), Fundamental Research Funds for the Central Universities, China (2017KFYXJJ107 and 2017KFYXJJ124), and the National Institutes of Health, USA (R01NS088627).

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Correspondence to Long-Jun Wu or Dai-Shi Tian.

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Qin, C., Zhou, LQ., Ma, XT. et al. Dual Functions of Microglia in Ischemic Stroke. Neurosci. Bull. 35, 921–933 (2019). https://doi.org/10.1007/s12264-019-00388-3

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