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Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 746068, 10 pages
http://dx.doi.org/10.1155/2013/746068
Review Article

Microglial Responses after Ischemic Stroke and Intracerebral Hemorrhage

1Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA
2Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA
3Department of Neurology, University of Connecticut Health Center and Hartford Hospital, Hartford, CT 06102, USA
4Department of Neurosurgery, Hartford Hospital, Hartford, CT 06102, USA

Received 10 May 2013; Revised 6 August 2013; Accepted 28 August 2013

Academic Editor: Jeffrey Zirger

Copyright © 2013 Roslyn A. Taylor and Lauren H. Sansing. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. Ginhoux, M. Greter, M. Leboeuf et al., “Fate mapping analysis reveals that adult microglia derive from primitive macrophages,” Science, vol. 330, no. 6005, pp. 841–845, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. B. Ajami, J. L. Bennett, C. Krieger, W. Tetzlaff, and F. M. V. Rossi, “Local self-renewal can sustain CNS microglia maintenance and function throughout adult life,” Nature Neuroscience, vol. 10, no. 12, pp. 1538–1543, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. U. Eyo and M. Dailey, “Microglia: key elements in neural development, plasticity, and pathology,” Journal of Neuroimmune Pharmacology, vol. 8, no. 3, pp. 494–509, 2013.
  4. Y. Suzuki, Q. Sa, M. Gehman, and E. Ochiai, “Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain,” Expert reviews in molecular medicine, vol. 13, p. e31, 2011. View at Scopus
  5. U. Puntener, S. G. Booth, V. H. Perry, and J. L. Teeling, “Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia,” Journal of Neuroinflammation, vol. 9, p. 146, 2012. View at Publisher · View at Google Scholar
  6. T. C. Browne, K. McQuillan, R. M. McManus, J. A. O. 'Reilly, K. H. Mills, and M. A. Lynch, “IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease,” The Journal of Immunology, vol. 190, no. 5, pp. 2241–2251, 2013. View at Publisher · View at Google Scholar
  7. N. Imamoto, S. Momosaki, M. Fujita et al., “[11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats,” Neuroimage, vol. 79, pp. 121–128, 2013. View at Publisher · View at Google Scholar
  8. J. Wang, “Preclinical and clinical research on inflammation after intracerebral hemorrhage,” Progress in Neurobiology, vol. 92, no. 4, pp. 463–477, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. M. Campanella, C. Sciorati, G. Tarozzo, and M. Beltramo, “Flow cytometric analysis of inflammatory cells in ischemic rat brain,” Stroke, vol. 33, no. 2, pp. 586–592, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Starossom, I. Mascanfroni, J. Imitola et al., “Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration,” Immunity, vol. 37, no. 2, pp. 249–263, 2012. View at Publisher · View at Google Scholar
  11. R. M. Ransohoff and M. A. Brown, “Innate immunity in the central nervous system,” Journal of Clinical Investigation, vol. 122, no. 4, pp. 1164–1171, 2012. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Kawanokuchi, K. Shimizu, A. Nitta et al., “Production and functions of IL-17 in microglia,” Journal of Neuroimmunology, vol. 194, no. 1-2, pp. 54–61, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Zhou, C. Wang, W. L. Yang, and P. Wang, “Microglial CD14 activated by iNOS contributes to neuroinflammation in cerebral ischemia,” Brain Research, vol. 1506, pp. 105–114, 2013. View at Publisher · View at Google Scholar
  14. I. Onwuekwe and B. Ezeala-Adikaibe, “Ischemic stroke and neuroprotection,” Annals of Medical and Health Sciences Research, vol. 2, no. 2, pp. 186–190, 2012. View at Publisher · View at Google Scholar
  15. A. Towfighi and J. L. Saver, “Stroke declines from third to fourth leading cause of death in the United States: historical perspective and challenges ahead,” Stroke, vol. 42, no. 8, pp. 2351–2355, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nature Medicine, vol. 17, no. 7, pp. 796–808, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Savitz and H. Mattle, “Advances in stroke: emerging therapies,” Stroke, vol. 44, no. 2, pp. 314–315, 2013. View at Publisher · View at Google Scholar
  18. X. Urra and A. Chamorro, “Emerging issues in acute ischemic stroke,” Journal of Neurology, vol. 260, no. 6, pp. 1687–1692, 2013.
  19. R. Gregersen, K. Lambertsen, and B. Finsen, “Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 1, pp. 53–65, 2000. View at Scopus
  20. E. Parada, J. Egea, I. Buendia et al., “The Microglial alpha7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2,” Antioxidants & Redox Signaling, vol. 19, no. 11, pp. 1135–1148, 2013. View at Publisher · View at Google Scholar
  21. E. Lehrmann, R. Kiefer, T. Christensen et al., “Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats,” Glia, vol. 24, no. 4, pp. 437–448, 1998.
  22. F. De Bilbao, D. Arsenijevic, T. Moll et al., “In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice,” Journal of Neurochemistry, vol. 110, no. 1, pp. 12–22, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Lalancette-Hébert, V. Swarup, J. Beaulieu et al., “Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury,” The Journal of Neuroscience, vol. 32, no. 30, pp. 10383–10395, 2012. View at Publisher · View at Google Scholar
  24. H. W. Morrison and J. A. Filosa, “A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion,” Journal of Neuroinflammation, vol. 10, p. 4, 2013. View at Publisher · View at Google Scholar
  25. D. Ito, K. Tanaka, S. Suzuki, T. Dembo, and Y. Fukuuchi, “Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain,” Stroke, vol. 32, no. 5, pp. 1208–1215, 2001. View at Scopus
  26. C. Perego, S. Fumagalli, and M.-G. De Simoni, “Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice,” Journal of Neuroinflammation, vol. 8, article 174, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. X. Hu, P. Li, Y. Guo et al., “Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia,” Stroke, vol. 43, no. 11, pp. 3063–3070, 2012.
  28. M. Schroeter, S. Jander, O. W. Witte, and G. Stoll, “Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex,” Neuroscience, vol. 89, no. 4, pp. 1367–1377, 1999. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Schroeter, M. A. Dennin, M. Walberer et al., “Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 6, pp. 1216–1225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Wiart, N. Davoust, J.-B. Pialat et al., “MRI monitoring of neuroinflammation in mouse focal ischemia,” Stroke, vol. 38, no. 1, pp. 131–137, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Denes, R. Vidyasagar, J. Feng et al., “Proliferating resident microglia after focal cerebral ischaemia in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 12, pp. 1941–1953, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Walberer, M. A. Rueger, M.-L. Simard et al., “Dynamics of neuroinflammation in the macrosphere model of arterio-arterial embolic focal ischemia: an approximation to human stroke patterns,” Experimental and Translational Stroke Medicine, vol. 2, no. 1, article 22, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Schilling, M. Besselmann, C. Leonhard, M. Mueller, E. B. Ringelstein, and R. Kiefer, “Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice,” Experimental Neurology, vol. 183, no. 1, pp. 25–33, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Schilling, M. Besselmann, M. Müller, J. K. Strecker, E. B. Ringelstein, and R. Kiefer, “Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice,” Experimental Neurology, vol. 196, no. 2, pp. 290–297, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. D. R. Getts, R. L. Terry, M. T. Getts et al., “Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis,” Journal of Experimental Medicine, vol. 205, no. 10, pp. 2319–2337, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. G. P. Schielke, G.-Y. Yang, B. D. Shivers, and A. L. Betz, “Reduced ischemic brain injury in interleukin-1β converting enzyme-deficient mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 18, no. 2, pp. 180–185, 1998. View at Scopus
  37. A.-G. Ceulemans, T. Zgavc, R. Kooijman, S. Hachimi-Idrissi, S. Sarre, and Y. Michotte, “The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia,” Journal of Neuroinflammation, vol. 7, article 74, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. S. A. Loddick, A. V. Turnbull, and N. J. Rothwell, “Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat,” Journal of Cerebral Blood Flow and Metabolism, vol. 18, no. 2, pp. 176–179, 1998. View at Scopus
  39. X. Wang, G. Z. Feuerstein, L. Xu et al., “Inhibition of tumor necrosis factor-α-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats,” Molecular Pharmacology, vol. 65, no. 4, pp. 890–896, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. M. K. McCoy and M. G. Tansey, “TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease,” Journal of Neuroinflammation, vol. 5, article 45, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. U. Heldmann, P. Thored, J.-H. Claasen, A. Arvidsson, Z. Kokaia, and O. Lindvall, “TNF-α antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain,” Experimental Neurology, vol. 196, no. 1, pp. 204–208, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. K. L. Lambertsen, B. H. Clausen, A. A. Babcock et al., “Microglia protect neurons against ischemia by synthesis of tumor necrosis factor,” Journal of Neuroscience, vol. 29, no. 5, pp. 1319–1330, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. U. Wesley, R. Vemuganti, E. Ayvaci, and R. Dempsey, “Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling,” Brain Research, vol. 1496, pp. 1–9, 2013. View at Publisher · View at Google Scholar
  44. Z. Wei, S. Chigurupati, T. V. Arumugam, D.-G. Jo, H. Li, and S. L. Chan, “Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia,” Stroke, vol. 42, no. 9, pp. 2589–2594, 2011. View at Publisher · View at Google Scholar · View at Scopus
  45. S. M. Lloyd-Burton, E. M. York, M. A. Anwar, A. J. Vincent, and A. J. Roskams, “SPARC regulates microgliosis and functional recovery following cortical ischemia,” The Journal of Neuroscience, vol. 33, no. 10, pp. 4468–4481, 2013. View at Publisher · View at Google Scholar
  46. J.-B. Kim, S. C. Joon, Y.-M. Yu et al., “HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain,” Journal of Neuroscience, vol. 26, no. 24, pp. 6413–6421, 2006. View at Publisher · View at Google Scholar · View at Scopus
  47. G. Faraco, S. Fossati, M. E. Bianchi et al., “High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo,” Journal of Neurochemistry, vol. 103, no. 2, pp. 590–603, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. S. Muhammad, W. Barakat, S. Stoyanov et al., “The HMGB1 receptor RAGE mediates ischemic brain damage,” Journal of Neuroscience, vol. 28, no. 46, pp. 12023–12031, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. G. A. Chapman, K. Moores, D. Harrison, C. A. Campbell, B. R. Stewart, and P. J. Strijbos, “Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage,” Journal of Neuroscience, vol. 20, no. 15, p. RC87, 2000. View at Scopus
  50. G. Tarozzo, M. Campanella, M. Ghiani, A. Bulfone, and M. Beltramo, “Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia-reperfusion brain injury in the rat,” European Journal of Neuroscience, vol. 15, no. 10, pp. 1663–1668, 2002. View at Publisher · View at Google Scholar · View at Scopus
  51. S. G. Soriano, L. S. Amaravadi, Y. F. Wang et al., “Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury,” Journal of Neuroimmunology, vol. 125, no. 1-2, pp. 59–65, 2002. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Fumagalli, C. Perego, F. Ortolano, and M. G. De Simoni, “CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice,” Glia, vol. 61, no. 6, pp. 827–842, 2013.
  53. Á. Dénes, S. Ferenczi, J. Halász, Z. Környei, and K. J. Kovács, “Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 10, pp. 1707–1721, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. R. Cipriani, P. Villa, G. Chece et al., “CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents,” Journal of Neuroscience, vol. 31, no. 45, pp. 16327–16335, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. F. Donovan, C. Pike, C. Cotman, and D. D. Cunningham, “Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities,” Journal of Neuroscience, vol. 17, no. 14, pp. 5316–5326, 1997. View at Scopus
  56. S. Fujimoto, H. Katsuki, M. Ohnishi, M. Takagi, T. Kume, and A. Akaike, “Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo,” Neuroscience, vol. 144, no. 2, pp. 694–701, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Ohnishi, H. Katsuki, S. Fujimoto, M. Takagi, T. Kume, and A. Akaike, “Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury,” Experimental Neurology, vol. 206, no. 1, pp. 43–52, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Ohnishi, H. Katsuki, Y. Izumi, T. Kume, Y. Takada-Takatori, and A. Akaike, “Mitogen-activated protein kinases support survival of activated microglia that mediate thrombin-induced striatal injury in organotypic slice culture,” Journal of Neuroscience Research, vol. 88, no. 10, pp. 2155–2164, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Wu, S. Yang, G. Xi et al., “Microglial activation and brain injury after intracerebral hemorrhage,” Acta Neurochirurgica, Supplementum, no. 105, pp. 59–65, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Xue, M. D. Hollenberg, and V. W. Yong, “Combination of thrombin and matrix metalloproteinase-9 exacerbates neurotoxicity in cell culture and intracerebral hemorrhage in mice,” Journal of Neuroscience, vol. 26, no. 40, pp. 10281–10291, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. A. H. Koeppen, A. C. Dickson, and J. Smith, “Heme oxygenase in experimental intracerebral hemorrhage: the benefit of tin-mesoporphyrin,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 6, pp. 587–597, 2004. View at Scopus
  62. J. Wang and S. Doré, “Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage,” Brain, vol. 130, no. 6, pp. 1643–1652, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Lin, Q. Yin, Q. Zhong et al., “Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage,” Journal of Neuroinflammation, vol. 9, article 46, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. J. K. Harrison, Y. Jiang, S. Chen et al., “Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 18, pp. 10896–10901, 1998. View at Publisher · View at Google Scholar · View at Scopus
  65. A. E. Cardona, E. P. Pioro, M. E. Sasse et al., “Control of microglial neurotoxicity by the fractalkine receptor,” Nature Neuroscience, vol. 9, no. 7, pp. 917–924, 2006. View at Publisher · View at Google Scholar · View at Scopus
  66. J. Zhu, Z. Zhou, Y. Liu, and J. Zheng, “Fractalkine and CX3CR1 are involved in the migration of intravenously grafted human bone marrow stromal cells toward ischemic brain lesion in rats,” Brain Research, vol. 1287, pp. 173–183, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. M. M. Donohue, K. Cain, D. Zierath, D. Shibata, P. M. Tanzi, and K. J. Becker, “Higher plasma fractalkine is associated with better 6-month outcome from ischemic stroke,” Stroke, vol. 43, no. 9, pp. 2300–2306, 2012. View at Publisher · View at Google Scholar
  68. K. Kobayashi, S. Imagama, T. Ohgomori et al., “Minocycline selectively inhibits M1 polarization of microglia,” Cell Death and Disease, vol. 4, p. e525, 2013. View at Publisher · View at Google Scholar
  69. Y. C. Weng and J. Kriz, “Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia,” Experimental Neurology, vol. 204, no. 1, pp. 433–442, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. Z. Liu, Y. Fan, S. J. Won et al., “Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia,” Stroke, vol. 38, no. 1, pp. 146–152, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Brenneman, S. Sharma, M. Harting et al., “Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 1, pp. 140–149, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. E. Keimpema, M. R. Fokkens, Z. Nagy et al., “Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats,” Neuropathology and Applied Neurobiology, vol. 35, no. 1, pp. 89–102, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. A. de Vasconcelos dos Santos, J. da Costa Reis, B. Diaz Paredes et al., “Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats,” Brain Research, vol. 1306, pp. 149–158, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Sharma, B. Yang, R. Strong et al., “Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke,” Journal of Neuroscience Research, vol. 88, no. 13, pp. 2869–2876, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Cardoso, E. Franco, C. de Souza, M. da Silva, A. Gouveia, and W. Gomes-Leal, “Minocycline treatment and bone marrow mononuclear cell transplantation after endothelin-1 induced striatal ischemia,” Inflammation, vol. 36, no. 1, pp. 197–205, 2013.
  76. E. C. S. Franco, M. M. Cardoso, A. Gouvêia, A. Pereira, and W. Gomes-Leal, “Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia,” Neuroscience Research, vol. 73, no. 2, pp. 122–132, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. N. Matsukawa, T. Yasuhara, K. Hara et al., “Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke,” BMC Neuroscience, vol. 10, article 1471, p. 126, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. D. Narantuya, A. Nagai, M. Abdullah et al., “Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement,” PLoS ONE, vol. 5, no. 7, Article ID e11746, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. E. Manno, “Update on intracerebral hemorrhage,” Continuum, vol. 18, no. 3, pp. 598–610, 2012.
  80. A. I. Qureshi, A. D. Mendelow, and D. F. Hanley, “Intracerebral haemorrhage,” The Lancet, vol. 373, no. 9675, pp. 1632–1644, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. L. B. Morgenstern, J. C. Hemphill III, C. Anderson et al., “Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association,” Stroke, vol. 41, no. 9, pp. 2108–2129, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. R. Keep, Y. Hua, and G. Xi, “Intracerebral haemorrhage: mechanisms of injury and therapeutic targets,” Lancet Neurology, vol. 11, no. 8, pp. 720–731, 2012.
  83. M. J. Carson, J. M. Doose, B. Melchior, C. D. Schmid, and C. C. Ploix, “CNS immune privilege: hiding in plain sight,” Immunological Reviews, vol. 213, no. 1, pp. 48–65, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. J. Aronowski and X. Zhao, “Molecular pathophysiology of cerebral hemorrhage: secondary brain injury,” Stroke, vol. 42, no. 6, pp. 1781–1786, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. J. Wang and S. Doré, “Inflammation after intracerebral hemorrhage,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 5, pp. 894–908, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. D. B. Kurland, V. Gerzanich, and J. M. Simard, “191 Heme induces microglial CXCL2 release-a mechanism of neutrophil-mediated injury after intracerebral hemorrhage,” Neurosurgery, vol. 60, supplement 1, p. 183, 2013.
  87. M. Xue and M. R. Del Bigio, “Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death,” Neuroscience Letters, vol. 283, no. 3, pp. 230–232, 2000. View at Publisher · View at Google Scholar · View at Scopus
  88. J. K. Wasserman, X. Zhu, and L. C. Schlichter, “Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment,” Brain Research, vol. 1180, no. 1, pp. 140–154, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. M. D. Hammond, Y. Ai, and L. H. Sansing, “Gr1+ macrophages and dendritic cells dominate the inflammatory infiltrate 12 h after experimental intracerebral hemorrhage,” Translational Stroke Research, vol. 3, 1, pp. 125–131, 2012. View at Publisher · View at Google Scholar · View at Scopus
  90. A. Yabluchanskiy, P. Sawle, S. Homer-Vanniasinkam, C. J. Green, and R. Motterlini, “Relationship between leukocyte kinetics and behavioral tests changes in the inflammatory process of hemorrhagic stroke recovery,” International Journal of Neuroscience, vol. 120, no. 12, pp. 765–773, 2010. View at Publisher · View at Google Scholar · View at Scopus
  91. L. H. Sansing, T. H. Harris, F. A. Welsh, S. E. Kasner, C. A. Hunter, and K. Kariko, “Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage,” Annals of Neurology, vol. 70, no. 4, pp. 646–656, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. I. Moxon-Emre and L. C. Schlichter, “Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage,” Journal of Neuropathology and Experimental Neurology, vol. 70, no. 3, pp. 218–235, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. L. H. Sansing, T. H. Harris, S. E. Kasner, C. A. Hunter, and K. Kariko, “Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage,” Acta Neurochirurgica, Supplementum, no. 111, pp. 173–178, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. H. Wu, T. Wu, X. Xu, J. Wang, and J. Wang, “Iron toxicity in mice with collagenase-induced intracerebral hemorrhage,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 5, pp. 1243–1250, 2011. View at Publisher · View at Google Scholar · View at Scopus
  95. M. C. Loftspring, C. Hansen, and J. F. Clark, “A novel brain injury mechanism after intracerebral hemorrhage: the interaction between heme products and the immune system,” Medical Hypotheses, vol. 74, no. 1, pp. 63–66, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. M. C. Loftspring, H. L. Johnson, R. Feng, A. J. Johnson, and J. F. Clark, “Unconjugated bilirubin contributes to early inflammation and edema after intracerebral hemorrhage,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 4, pp. 1133–1142, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. H. Fang, P. F. Wang, Y. Zhou, Y. C. Wang, and Q. W. Yang, “Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury,” Journal of Neuroinflammation, vol. 10, p. 27, 2013. View at Publisher · View at Google Scholar
  98. Y. Zhou, K.-L. Xiong, S. Lin et al., “Elevation of high-mobility group protein box-1 in serum correlates with severity of acute intracerebral hemorrhage,” Mediators of Inflammation, vol. 2010, Article ID 142458, 6 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. C. Lei, S. Lin, C. Zhang et al., “High-mobility group box1 protein promotes neuroinflammation after intracerebral hemorrhage in rats,” Neuroscience, vol. 228, pp. 190–199, 2013. View at Publisher · View at Google Scholar
  100. A. Szymanska, J. Biernaskie, D. Laidley, S. Granter-Button, and D. Corbett, “Minocycline and intracerebral hemorrhage: influence of injury severity and delay to treatment,” Experimental Neurology, vol. 197, no. 1, pp. 189–196, 2006. View at Publisher · View at Google Scholar · View at Scopus
  101. J. K. Wasserman and L. C. Schlichter, “Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat,” Experimental Neurology, vol. 207, no. 2, pp. 227–237, 2007. View at Publisher · View at Google Scholar · View at Scopus
  102. J. Wu, S. Yang, G. Xi, G. Fu, R. F. Keep, and Y. Hua, “Minocycline reduces intracerebral hemorrhage-induced brain injury,” Neurological Research, vol. 31, no. 2, pp. 183–188, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. X. Zhao, G. Sun, J. Zhang et al., “Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor γ in microglia/macrophages,” Annals of Neurology, vol. 61, no. 4, pp. 352–362, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. X. Zhao, J. Grotta, N. Gonzales, and J. Aronowski, “Hematoma resolution as a therapeutic target: the role of microglia/macrophages,” Stroke, vol. 40, no. 3, pp. S92–S94, 2009. View at Publisher · View at Google Scholar · View at Scopus