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  • Review Article
  • Published:

Modulators of microglial activation and polarization after intracerebral haemorrhage

Nature Reviews Neurology volume 13, pages 420–433 (2017)Cite this article

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This article has been updated

Key Points

  • Microglial polarization after intracerebral haemorrhage (ICH) modulates microglial phagocytic function and might affect haematoma clearance

  • Activation of microglia to an M1-like phenotype occurs mainly in the acute phase after ICH

  • M2-like microglial responses occur in the subacute and chronic phase and might contribute to phagocytosis of cell debris and haematoma clearance

  • Microglial polarization can be regulated by transcription factors, chemokines, receptors and their signalling pathways, and interactions between microglia and other cells in the brain (T lymphocytes, neurons, astrocytes and oligodendrocytes)

  • Data from clinical trials and preclinical studies suggest that targeting of microglial phenotype switching represents a new research direction for ICH treatment

Abstract

Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment. Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH. Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes. This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines. Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance. Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology. This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways. Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described. Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair.

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Figure 1: Dynamic changes in microglial marker levels and profiles over time after intracerebral haemorrhage.
Figure 2: Modulators of microglial polarization and phagocytosis after intracerebral haemorrhage.

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Change history

  • 01 June 2017

    In the initial version of this article, the third sentence in the section "Prostaglandin E2 receptors" included an incorrect reference citation (ref. 151 instead of ref. 150). This error has been corrected in the HTML and PDF versions of the article.

References

  1. Feigin, V. L., Lawes, C. M., Bennett, D. A., Barker-Collo, S. L. & Parag, V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 8, 355–369 (2009).

    Article  PubMed  Google Scholar 

  2. Steiner, T. et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int. J. Stroke 9, 840–855 (2014).

    Article  PubMed  Google Scholar 

  3. Kim, J. Y. & Bae, H. J. Spontaneous intracerebral hemorrhage: management. J. Stroke 19, 28–39 (2017).

    Article  PubMed  Google Scholar 

  4. Thabet, A. M., Kottapally, M. & Hemphill, J. C. III. Management of intracerebral hemorrhage. Handb. Clin. Neurol. 140, 177–194 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Hemphill, J. C. III et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 46, 2032–2060 (2015).

    Article  PubMed  Google Scholar 

  6. Wang, J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog. Neurobiol. 92, 463–477 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lan, X., Liu, R., Sun, L., Zhang, T. & Du, G. Methyl salicylate 2-O-β-D-lactoside, a novel salicylic acid analogue, acts as an anti-inflammatory agent on microglia and astrocytes. J. Neuroinflammation 8, 98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang, J. et al. Bone marrow mononuclear cells exert long-term neuroprotection in a rat model of ischemic stroke by promoting arteriogenesis and angiogenesis. Brain Behav. Immun. 34, 56–66 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Balami, J. S., Fricker, R. A. & Chen, R. Stem cell therapy for ischaemic stroke: translation from preclinical studies to clinical treatment. CNS Neurol. Disord. Drug Targets 12, 209–219 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Larochelle, A., Bellavance, M. A., Michaud, J. P. & Rivest, S. Bone marrow-derived macrophages and the CNS: an update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders. Biochim. Biophys. Acta 1862, 310–322 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Jiang, C. et al. Comparison of the therapeutic effects of bone marrow mononuclear cells and microglia for permanent cerebral ischemia. Behav. Brain Res. 250, 222–229 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhou, Y., Wang, Y., Wang, J., Anne Stetler, R. & Yang, Q. W. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog. Neurobiol. 115, 25–44 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, Z. et al. Microglial polarization and inflammatory mediators after intracerebral hemorrhage. Mol. Neurobiol. 54, 1874–1886 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Mendelow, A. D. et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 382, 397–408 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gonzales, N. R. Ongoing clinical trials in intracerebral hemorrhage. Stroke 44, S70–S73 (2013).

    Article  PubMed  Google Scholar 

  16. Xiong, X. Y., Liu, L. & Yang, Q. W. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog. Neurobiol. 142, 23–44 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Fumagalli, S., Perego, C., Pischiutta, F., Zanier, E. R. & De Simoni, M. G. The ischemic environment drives microglia and macrophage function. Front. Neurol. 6, 81 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chhor, V. et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav. Immun. 32, 70–85 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hu, X. et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43, 3063–3070 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Wang, G. et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J. Cereb. Blood Flow Metab. 33, 1864–1874 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kroner, A. et al. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83, 1098–1116 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Hayakawa, K. et al. Lipopolysaccharide preconditioning facilitates M2 activation of resident microglia after spinal cord injury. J. Neurosci. Res. 92, 1647–1658 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Kigerl, K. A. et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435–13444 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Han, L. et al. Rosiglitazone promotes white matter integrity and long-term functional recovery after focal cerebral ischemia. Stroke 46, 2628–2636 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kumar, A. et al. Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol. Aging 34, 1397–1411 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Wang, G. et al. HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. Proc. Natl Acad. Sci. USA 112, 2853–2858 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Turtzo, L. C. et al. Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J. Neuroinflammation 11, 82 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu, X. et al. Microglial and macrophage polarization — new prospects for brain repair. Nat. Rev. Neurol. 11, 56–64 (2015).

    Article  PubMed  Google Scholar 

  29. Kumar, A., Alvarez-Croda, D. M., Stoica, B. A., Faden, A. I. & Loane, D. J. Microglial/macrophage polarization dynamics following traumatic brain injury. J. Neurotrauma 33, 1732–1750 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Perego, C. et al. Macrophages are essential for maintaining a M2 protective response early after ischemic brain injury. Neurobiol. Dis. 96, 284–293 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Benson, M. J., Manzanero, S. & Borges, K. Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia 56, 895–905 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Casella, G. et al. IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo. J. Neuroinflammation 13, 139 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, C. C., Nakamura, M. C. & Hsieh, C. L. Brain trauma elicits non-canonical macrophage activation states. J. Neuroinflammation 13, 117 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, J. & Tsirka, S. E. Tuftsin fragment 1–3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 36, 613–618 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, J., Rogove, A. D., Tsirka, A. E. & Tsirka, S. E. Protective role of tuftsin fragment 1–3 in an animal model of intracerebral hemorrhage. Ann. Neurol. 54, 655–664 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Liew, H. K. et al. Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats. J. Neuroinflammation 9, 13 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, J. & Dore, S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 130, 1643–1652 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhao, X. et al. Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. Brain Behav. Immun. 46, 293–310 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jiang, C. et al. Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice. Neurobiol. Aging 42, 13–24 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tischer, J. et al. Inhomogeneous distribution of Iba-1 characterizes microglial pathology in Alzheimer's disease. Glia 64, 1562–1572 (2016).

    Article  PubMed  Google Scholar 

  42. Yang, Y. et al. Thrombin-induced microglial activation impairs hippocampal neurogenesis and spatial memory ability in mice. Behav. Brain Funct. 11, 30 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hammond, M. D., Ai, Y. & Sansing, L. H. Gr1+ macrophages and dendritic cells dominate the inflammatory infiltrate 12 hours after experimental intracerebral hemorrhage. Transl. Stroke Res. 3, s125–s131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cheng, T. et al. Cerebroprotection of flavanol (–)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways. Free Radic. Biol. Med. 92, 15–28 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. Zhou, K. et al. Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis. J. Cereb. Blood Flow Metab. 37, 967–979 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Greter, M., Lelios, I. & Croxford, A. L. Microglia versus myeloid cell nomenclature during brain inflammation. Front. Immunol. 6, 249 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mracsko, E. et al. Leukocyte invasion of the brain after experimental intracerebral hemorrhage in mice. Stroke 45, 2107–2114 (2014).

    Article  PubMed  Google Scholar 

  48. Zhang, Z. et al. NF-κB activation and cell death after intracerebral hemorrhage in patients. Neurol. Sci. 35, 1097–1102 (2014).

    Article  PubMed  Google Scholar 

  49. Wu, H. et al. Dynamic changes of inflammatory markers in brain after hemorrhagic stroke in humans: a postmortem study. Brain Res. 1342, 111–117 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Liesz, A. et al. Comparison of humoral neuroinflammation and adhesion molecule expression in two models of experimental intracerebral hemorrhage. Exp. Transl. Stroke Med. 3, 11 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Matsushita, H. et al. Suppression of CXCL2 upregulation underlies the therapeutic effect of the retinoid Am80 on intracerebral hemorrhage in mice. J. Neurosci. Res. 92, 1024–1034 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Yang, S. et al. Hemoglobin-induced nitric oxide synthase overexpression and nitric oxide production contribute to blood–brain barrier disruption in the rat. J. Mol. Neurosci. 51, 352–363 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Wasserman, J. K., Zhu, X. & Schlichter, L. C. Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment. Brain Res. 1180, 140–154 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Lin, S. et al. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J. Neuroinflammation 9, 46 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Xie, R. X. et al. Carnosine attenuates brain oxidative stress and apoptosis after intracerebral hemorrhage in rats. Neurochem. Res. 42, 541–551 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Zhang, Y. et al. Quercetin promotes neuronal and behavioral recovery by suppressing inflammatory response and apoptosis in a rat model of intracerebral hemorrhage. Neurochem. Res. 40, 195–203 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Yang, S. S. et al. High morphologic plasticity of microglia/macrophages following experimental intracerebral hemorrhage in rats. Int. J. Mol. Sci. 17, E1181 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. King, M. D., Alleyne, C. H. Jr & Dhandapani, K. M. TNF-α receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci. Lett. 542, 92–96 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhao, H., Garton, T., Keep, R. F., Hua, Y. & Xi, G. Microglia/macrophage polarization after experimental intracerebral hemorrhage. Transl. Stroke Res. 6, 407–409 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Taylor, R. A. et al. TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J. Clin. Invest. 127, 280–292 (2017).

    Article  PubMed  Google Scholar 

  61. Ma, L. et al. Blocking B7-1/CD28 pathway diminished long-range brain damage by regulating the immune and inflammatory responses in a mouse model of intracerebral hemorrhage. Neurochem. Res. 41, 1673–1683 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Lan, X. et al. Pinocembrin protects hemorrhagic brain primarily by inhibiting Toll-like receptor 4 and reducing M1 phenotype microglia. Brain Behav. Immun. 61, 326–339 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Rodriguez-Yanez, M. et al. Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage. J. Neuroimmunol. 247, 75–80 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Lively, S. & Schlichter, L. C. Age-related comparisons of evolution of the inflammatory response after intracerebral hemorrhage in rats. Transl. Stroke Res. 3, 132–146 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, Y. C. et al. Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage. Ann. Neurol. 75, 876–889 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Wang, Y. et al. TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proc. Natl Acad. Sci. USA 113, E884–E893 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Xiong, X. Y. et al. Toll-like receptor 4/MyD88-mediated signaling of hepcidin expression causing brain iron accumulation, oxidative injury, and cognitive impairment after intracerebral hemorrhage. Circulation 134, 1025–1038 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Wang, Y. C. et al. Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury. Stroke 44, 2545–2552 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Sansing, L. H. et al. Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann. Neurol. 70, 646–656 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Teng, W., Wang, L., Xue, W. & Guan, C. Activation of TLR4-mediated NFκB signaling in hemorrhagic brain in rats. Mediators Inflamm. 2009, 473276 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Yang, Z. et al. Toll-like receptor-4-mediated autophagy contributes to microglial activation and inflammatory injury in mouse models of intracerebral haemorrhage. Neuropathol. Appl. Neurobiol. 41, e95–e106 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Lian, H. et al. Astrocyte–microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer's disease. J. Neurosci. 36, 577–589 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Garrett, M. C. et al. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res. 1298, 171–177 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Yang, S. et al. The role of complement C3 in intracerebral hemorrhage-induced brain injury. J. Cereb. Blood Flow Metab. 26, 1490–1495 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Yuan, B. et al. C5a/C5aR pathway plays a vital role in brain inflammatory injury via initiating Fgl-2 in intracerebral hemorrhage. Mol. Neurobiol. http://dx.doi.org/10.1007/s12035-016-0141-7 (2016).

  76. Li, G. et al. Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage. Clin. Exp. Immunol. 175, 285–295 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen, Z. & Trapp, B. D. Microglia and neuroprotection. J. Neurochem. 136 (Suppl. 1), 10–17 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Zhao, X. et al. Neuronal interleukin-4 as a modulator of microglial pathways and ischemic brain damage. J. Neurosci. 35, 11281–11291 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zanier, E. R. et al. Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice. J. Neurotrauma 33, 1060–1072 (2015).

    Article  PubMed  Google Scholar 

  80. Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A. & Hymowitz, S. G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Avdic, S. et al. Human cytomegalovirus interleukin-10 polarizes monocytes toward a deactivated M2c phenotype to repress host immune responses. J. Virol. 87, 10273–10282 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Koscso, B. et al. Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages. J. Leukoc. Biol. 94, 1309–1315 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. David, S. & Kroner, A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat. Rev. Neurosci. 12, 388–399 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Capsoni, F. et al. IL-10 up-regulates human monocyte phagocytosis in the presence of IL-4 and IFN-γ. J. Leukoc. Biol. 58, 351–358 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Leidi, M. et al. M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than M1 cells in vitro. J. Immunol. 182, 4415–4422 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Donnelly, R. P., Dickensheets, H. & Finbloom, D. S. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J. Interferon Cytokine Res. 19, 563–573 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7, 454–465 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Dziedzic, T. et al. Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in blood. Stroke 33, 2334–2335 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Wang, K. W. et al. Molecular biomarker of inflammatory response is associated with rebleeding in spontaneous intracerebral hemorrhage. Eur. Neurol. 66, 322–327 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Shi, L. et al. Increased frequency of circulating regulatory T cells in patients with acute cerebral hemorrhage. Neurosci. Lett. 591, 115–120 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Liu, B. et al. CD163/hemoglobin oxygenase-1 pathway regulates inflammation in hematoma surrounding tissues after intracerebral hemorrhage. J. Stroke Cerebrovasc. Dis. 24, 2800–2809 (2015).

    Article  PubMed  Google Scholar 

  92. Ewen, T. et al. Neuroprotective effect of atorvastatin involves suppression of TNF-α and upregulation of IL-10 in a rat model of intracerebral hemorrhage. Cell Biochem. Biophys. 66, 337–346 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Gao, L. et al. Transplanted neural stem cells modulate regulatory T, γδ T cells and corresponding cytokines after intracerebral hemorrhage in rats. Int. J. Mol. Sci. 15, 4431–4441 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yang, J. et al. Interleukin-4 ameliorates the functional recovery of intracerebral hemorrhage through the alternative activation of microglia/macrophage. Front. Neurosci. 10, 61 (2016).

    PubMed  PubMed Central  Google Scholar 

  95. Neve, B. P., Fruchart, J. C. & Staels, B. Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochem. Pharmacol. 60, 1245–1250 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Zhao, X., Zhang, Y., Strong, R., Grotta, J. C. & Aronowski, J. 15D-prostaglandin J2 activates peroxisome proliferator-activated receptor-γ, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J. Cereb. Blood Flow Metab. 26, 811–820 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Zhao, X. et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor γ in microglia/macrophages. Ann. Neurol. 61, 352–362 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Zhao, X., Grotta, J., Gonzales, N. & Aronowski, J. Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke 40, S92–S94 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Chang, C. F. et al. Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. Neurobiol. Dis. 103, 54–69 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. An, W. L. et al. Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am. J. Pathol. 163, 591–607 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pan, T. et al. Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16–25 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S. & Greene, L. A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30, 1166–1175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen, S. et al. Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. J. Cereb. Blood Flow Metab. 27, 939–949 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. You, W. et al. Inhibition of mammalian target of rapamycin attenuates early brain injury through modulating microglial polarization after experimental subarachnoid hemorrhage in rats. J. Neurol. Sci. 367, 224–231 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. Lu, Q. et al. Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat. J. Neuroinflammation 11, 44 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, J. P. & Zhang, M. Y. Role for target of rapamycin (mTOR) signal pathway in regulating neuronal injury after intracerebral hemorrhage. Cell. Physiol. Biochem. 41, 145–153 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. Wan, S. et al. Microglia activation and polarization after intracerebral hemorrhage in mice: the role of protease-activated receptor-1. Transl. Stroke Res. 7, 478–487 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Han, X. et al. Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury. J. Cereb. Blood Flow Metab. 36, 1059–1074 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cao, S. et al. Hematoma changes during clot resolution after experimental intracerebral hemorrhage. Stroke 47, 1626–1631 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Zhao, X. et al. Dimethyl fumarate protects brain from damage produced by intracerebral hemorrhage by mechanism involving Nrf2. Stroke 46, 1923–1928 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yao, Y. & Tsirka, S. E. The CCL2–CCR2 system affects the progression and clearance of intracerebral hemorrhage. Glia 60, 908–918 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  113. McGilvray, I. D., Serghides, L., Kapus, A., Rotstein, O. D. & Kain, K. C. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 96, 3231–3240 (2000).

    CAS  PubMed  Google Scholar 

  114. Husemann, J., Loike, J. D., Anankov, R., Febbraio, M. & Silverstein, S. C. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, 195–205 (2002).

    Article  PubMed  Google Scholar 

  115. Fang, H. et al. CD36-mediated hematoma absorption following intracerebral hemorrhage: negative regulation by TLR4 signaling. J. Immunol. 192, 5984–5992 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ren, Y., Silverstein, R. L., Allen, J. & Savill, J. CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis. J. Exp. Med. 181, 1857–1862 (1995).

    Article  CAS  PubMed  Google Scholar 

  117. Li, X. et al. Prostaglandin E2 receptor subtype 2 regulation of scavenger receptor CD36 modulates microglial Aβ42 phagocytosis. Am. J. Pathol. 185, 230–239 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zamora, C. et al. Functional consequences of CD36 downregulation by TLR signals. Cytokine 60, 257–265 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Olsson, M., Nilsson, A. & Oldenborg, P. A. Target cell CD47 regulates macrophage activation and erythrophagocytosis. Transfus. Clin. Biol. 13, 39–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Matozaki, T., Murata, Y., Okazawa, H. & Ohnishi, H. Functions and molecular mechanisms of the CD47–SIRPα signalling pathway. Trends Cell Biol. 19, 72–80 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Olsson, M., Nilsson, A. & Oldenborg, P. A. Dose-dependent inhibitory effect of CD47 in macrophage uptake of IgG-opsonized murine erythrocytes. Biochem. Biophys. Res. Commun. 352, 193–197 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ni, W., Mao, S., Xi, G., Keep, R. F. & Hua, Y. Role of erythrocyte CD47 in intracerebral hematoma clearance. Stroke 47, 505–511 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hume, D. A. The many alternative faces of macrophage activation. Front. Immunol. 6, 370 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Taetzsch, T. et al. Redox regulation of NF-κB p50 and M1 polarization in microglia. Glia 63, 423–440 (2015).

    Article  PubMed  Google Scholar 

  126. Zhang, Z. L. et al. Nuclear factor-κB activation in perihematomal brain tissue correlates with outcome in patients with intracerebral hemorrhage. J. Neuroinflammation 12, 53 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Arimoto, K. I. et al. STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nat. Struct. Mol. Biol. 24, 279–289 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Jeon, S. B. et al. Galectin-3 exerts cytokine-like regulatory actions through the JAK–STAT pathway. J. Immunol. 185, 7037–7046 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Das, A. et al. Transcriptome sequencing of microglial cells stimulated with TLR3 and TLR4 ligands. BMC Genomics 16, 517 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Leopold Wager, C. M. et al. STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans. Infect. Immun. 83, 4513–4527 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Qin, H. et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc. Natl Acad. Sci. USA 109, 5004–5009 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Kim, C. K. et al. Detrimental effects of leptin on intracerebral hemorrhage via the STAT3 signal pathway. J. Cereb. Blood Flow Metab. 33, 944–953 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Freilich, R. W., Woodbury, M. E. & Ikezu, T. Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia. PLoS ONE 8, e79416 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Uhlemann, R. et al. Actin dynamics shape microglia effector functions. Brain Struct. Funct. 221, 2717–2734 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Ferreira, R., Lively, S. & Schlichter, L. C. IL-4 type 1 receptor signaling up-regulates KCNN4 expression, and increases the KCa3.1 current and its contribution to migration of alternative-activated microglia. Front. Cell. Neurosci. 8, 183 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang, J. et al. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic. Biol. Med. 43, 408–414 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Shang, H. et al. Time course of Keap1–Nrf2 pathway expression after experimental intracerebral haemorrhage: correlation with brain oedema and neurological deficit. Free Radic. Res. 47, 368–375 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Zhao, X. et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J. Neurochem. 133, 144–152 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Schallner, N. et al. Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J. Clin. Invest. 125, 2609–2625 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Naito, Y., Takagi, T. & Higashimura, Y. Heme oxygenase-1 and anti-inflammatory M2 macrophages. Arch. Biochem. Biophys. 564, 83–88 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Lee, S. et al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat. Chem. Biol. 10, 1055–1060 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Kim, J. B. et al. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J. Neurosci. 26, 6413–6421 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Karuppagounder, V. et al. Modulation of macrophage polarization and HMGB1–TLR2/TLR4 cascade plays a crucial role for cardiac remodeling in senescence-accelerated prone mice. PLoS ONE 11, e0152922 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhou, Y. et al. Elevation of high-mobility group protein box-1 in serum correlates with severity of acute intracerebral hemorrhage. Mediators Inflamm. 2010, 142458 (2010).

    PubMed  PubMed Central  Google Scholar 

  146. Ohnishi, M. et al. HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats. Neuropharmacology 61, 975–980 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Lei, C. et al. High-mobility group box 1 protein promotes neuroinflammation after intracerebral hemorrhage in rats. Neuroscience 228, 190–199 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Wu, H. et al. Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice. J. Cereb. Blood Flow Metab. 37, 39–51 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Li, D. et al. Blockade of high mobility group box-1 signaling via the receptor for advanced glycation end-products ameliorates inflammatory damage after acute intracerebral hemorrhage. Neurosci. Lett. 609, 109–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Singh, N. et al. Role of PGE2 EP1 receptor in intracerebral hemorrhage-induced brain injury. Neurotox. Res. 24, 549–559 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Leclerc, J. L., Lampert, A. S., Diller, M. A. & Doré, S. Genetic deletion of the prostaglandin E2 E prostanoid receptor subtype 3 improves anatomical and functional outcomes after intracerebral hemorrhage. Eur. J. Neurosci. 41, 1381–1391 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Wu, H. et al. PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice. Neurobiol. Aging 36, 1439–1450 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. van Echten-Deckert, G., Hagen-Euteneuer, N., Karaca, I. & Walter, J. Sphingosine-1-phosphate: boon and bane for the brain. Cell. Physiol. Biochem. 34, 148–157 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Yung, Y. C., Stoddard, N. C., Mirendil, H. & Chun, J. Lysophosphatidic acid signaling in the nervous system. Neuron 85, 669–682 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Tham, C. S., Lin, F. F., Rao, T. S., Yu, N. & Webb, M. Microglial activation state and lysophospholipid acid receptor expression. Int. J. Dev. Neurosci. 21, 431–443 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Noda, H., Takeuchi, H., Mizuno, T. & Suzumura, A. Fingolimod phosphate promotes the neuroprotective effects of microglia. J. Neuroimmunol. 256, 13–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Marfia, G. et al. The adipose mesenchymal stem cell secretome inhibits inflammatory responses of microglia: evidence for an involvement of sphingosine-1-phosphate signalling. Stem Cells Dev. 25, 1095–1107 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Gao, F. et al. Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model. Pharmacol. Biochem. Behav. 103, 187–196 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Serdar, M. et al. Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia. Brain Behav. Immun. 52, 106–119 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Rothhammer, V. et al. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc. Natl Acad. Sci. USA 114, 2012–2017 (2017).

    Article  CAS  PubMed  Google Scholar 

  161. Rolland, W. B. II et al. FTY720 is neuroprotective and improves functional outcomes after intracerebral hemorrhage in mice. Acta Neurochir. Suppl. 111, 213–217 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Rolland, W. B. et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp. Neurol. 241, 45–55 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Fu, Y. et al. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol. 71, 1092–1101 (2014).

    Article  PubMed  Google Scholar 

  164. Lu, L. et al. Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res. 1555, 89–96 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02002390 (2014).

  166. Chen, S. et al. Regulatory T cell in stroke: a new paradigm for immune regulation. Clin. Dev. Immunol. 2013, 689827 (2013).

    PubMed  PubMed Central  Google Scholar 

  167. Gong, G. et al. Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2-induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection. Blood 113, 837–845 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhong, Q. et al. Interleukin-23 secreted by activated macrophages drives γδT cell production of interleukin-17 to aggravate secondary injury after intracerebral hemorrhage. J. Am. Heart Assoc. 5, e004340 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Yang, Z. et al. Regulatory T cells inhibit microglia activation and protect against inflammatory injury in intracerebral hemorrhage. Int. Immunopharmacol. 22, 522–525 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Mao, L. L. et al. Adoptive regulatory T-cell therapy attenuates perihematomal inflammation in a mouse model of experimental intracerebral hemorrhage. Cell. Mol. Neurobiol.http://dx.doi.org/10.1007/s10571-016-0429-1 (2016).

  171. Paolicelli, R. C., Bisht, K. & Tremblay, M. E. Fractalkine regulation of microglial physiology and consequences on the brain and behavior. Front. Cell. Neurosci. 8, 129 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Limatola, C. & Ransohoff, R. M. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front. Cell. Neurosci. 8, 229 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wolf, Y., Yona, S., Kim, K. W. & Jung, S. Microglia, seen from the CX3CR1 angle. Front. Cell. Neurosci. 7, 26 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Zabel, M. K. et al. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1–CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 64, 1479–1491 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  176. Tarozzo, G., Campanella, M., Ghiani, M., Bulfone, A. & Beltramo, M. Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia–reperfusion brain injury in the rat. Eur. J. Neurosci. 15, 1663–1668 (2002).

    Article  PubMed  Google Scholar 

  177. Zhu, J., Zhou, Z., Liu, Y. & Zheng, J. Fractalkine and CX3CR1 are involved in the migration of intravenously grafted human bone marrow stromal cells toward ischemic brain lesion in rats. Brain Res. 1287, 173–183 (2009).

    Article  CAS  PubMed  Google Scholar 

  178. Soriano, S. G. et al. Mice deficient in fractalkine are less susceptible to cerebral ischemia–reperfusion injury. J. Neuroimmunol. 125, 59–65 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Gaetani, P. et al. Immunohistohemical expression of the chemokine fractalkine and its receptor in the human brain cortex after severe traumatic brain injury and brain hemorrhage. J. Neurosurg. Sci. 57, 55–62 (2013).

    CAS  PubMed  Google Scholar 

  180. Taylor, R. A., Hammond, M. D., Ai, Y. & Sansing, L. H. CX3CR1 signaling on monocytes is dispensable after intracerebral hemorrhage. PLoS ONE 9, e114472 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  182. Nash, B. et al. Functional duality of astrocytes in myelination. J. Neurosci. 31, 13028–13038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. McKimmie, C. S. & Graham, G. J. Astrocytes modulate the chemokine network in a pathogen-specific manner. Biochem. Biophys. Res. Commun. 394, 1006–1011 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. Allaman, I., Belanger, M. & Magistretti, P. J. Astrocyte–neuron metabolic relationships: for better and for worse. Trends Neurosci. 34, 76–87 (2011).

    Article  CAS  PubMed  Google Scholar 

  185. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. Rosell, A. et al. Brain perihematoma genomic profile following spontaneous human intracerebral hemorrhage. PLoS ONE 6, e16750 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Carmichael, S. T. et al. Genomic profiles of damage and protection in human intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 28, 1860–1875 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Yao, Y. & Tsirka, S. E. Chemokines and their receptors in intracerebral hemorrhage. Transl. Stroke Res. 3, 70–79 (2012).

    Article  CAS  PubMed  Google Scholar 

  189. Lu, A. et al. Brain genomics of intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 26, 230–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Hernandez-Rabaza, V. et al. Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia. J. Neuroinflammation 13, 83 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. He, M. et al. Astrocyte-derived CCL2 is associated with M1 activation and recruitment of cultured microglial cells. Cell. Physiol. Biochem. 38, 859–870 (2016).

    Article  CAS  PubMed  Google Scholar 

  192. Joseph, M. J., Caliaperumal, J. & Schlichter, L. C. After intracerebral hemorrhage, oligodendrocyte precursors proliferate and differentiate inside white-matter tracts in the rat striatum. Transl. Stroke Res. 7, 192–208 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zhao, X. et al. Neuroprotective role of haptoglobin after intracerebral hemorrhage. J. Neurosci. 29, 15819–15827 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Shukla, S. M. & Sharma, S. K. Sinomenine inhibits microglial activation by Aβ and confers neuroprotection. J. Neuroinflammation 8, 117 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Qian, L. et al. Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. J. Neuroinflammation 4, 23 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Xu, M., Liu, L., Qi, C., Deng, B. & Cai, X. Sinomenine versus NSAIDs for the treatment of rheumatoid arthritis: a systematic review and meta-analysis. Planta Med. 74, 1423–1429 (2008).

    Article  CAS  PubMed  Google Scholar 

  198. Yang, Z. et al. Sinomenine inhibits microglia activation and attenuates brain injury in intracerebral hemorrhage. Mol. Immunol. 60, 109–114 (2014).

    Article  CAS  PubMed  Google Scholar 

  199. Shi, H. et al. Sinomenine enhances microglia M2 polarization and attenuates inflammatory injury in intracerebral hemorrhage. J. Neuroimmunol. 299, 28–34 (2016).

    Article  CAS  PubMed  Google Scholar 

  200. Kim, K. et al. The effect of human umbilical cord blood-derived mesenchymal stem cells in a collagenase-induced intracerebral hemorrhage rat model. Exp. Neurobiol. 24, 146–155 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02274428 (2017).

  202. Wang, J. & Dore, S. Inflammation after intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 27, 894–908 (2007).

    Article  CAS  PubMed  Google Scholar 

  203. Wang, J. & Tsirka, S. E. Contribution of extracellular proteolysis and microglia to intracerebral hemorrhage. Neurocrit. Care 3, 77–85 (2005).

    Article  CAS  PubMed  Google Scholar 

  204. Komohara, Y., Jinushi, M. & Takeya, M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 105, 1–8 (2014).

    Article  CAS  PubMed  Google Scholar 

  205. Siddiqui, T. A., Lively, S. & Schlichter, L. C. Complex molecular and functional outcomes of single versus sequential cytokine stimulation of rat microglia. J. Neuroinflammation 13, 66 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Vogel, D. Y. et al. Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation. J. Neuroinflammation 11, 23 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Guedj, K. et al. M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis. Cardiovasc. Res. 101, 434–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  208. Zhong, T. Y. et al. Hemocyanins stimulate innate immunity by inducing different temporal patterns of proinflammatory cytokine expression in macrophages. J. Immunol. 196, 4650–4662 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Tarassishin, L., Suh, H. S. & Lee, S. C. Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. J. Neuroinflammation 8, 187 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Chong, B. F. et al. A subset of CD163+ macrophages displays mixed polarizations in discoid lupus skin. Arthritis Res. Ther. 17, 324 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Hennessy, E., Griffin, E. W. & Cunningham, C. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-α. J. Neurosci. 35, 8411–8422 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Sielska, M. et al. Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response. J. Pathol. 230, 310–321 (2013).

    Article  CAS  PubMed  Google Scholar 

  213. Suenaga, J. et al. White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke. Exp. Neurol. 272, 109–119 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Wachholz, S. et al. Microglia activation is associated with IFN-α induced depressive-like behavior. Brain Behav. Immun. 55, 105–113 (2015).

    Article  CAS  PubMed  Google Scholar 

  215. Okuneva, O. et al. Abnormal microglial activation in the Cstb−/− mouse, a model for progressive myoclonus epilepsy, EPM1. Glia 63, 400–411 (2015).

    Article  PubMed  Google Scholar 

  216. Stojakovic, A. et al. Role of the IL-1 pathway in dopaminergic neurodegeneration and decreased voluntary movement. Mol. Neurobiol.http://dx.doi.org/10.1007/s12035-016-9988-x (2016).

  217. Liu, X. et al. Interleukin-4 is essential for microglia/macrophage M2 polarization and long-term recovery after cerebral ischemia. Stroke 47, 498–504 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Peferoen, L. A. et al. Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis. J. Neuropathol. Exp. Neurol. 74, 48–63 (2015).

    Article  CAS  PubMed  Google Scholar 

  219. Yamashita, U. & Kuroda, E. Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit. Rev. Immunol. 22, 105–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  220. Evans, B. J., Haskard, D. O., Sempowksi, G. & Landis, R. C. Evolution of the macrophage CD163 phenotype and cytokine profiles in a human model of resolving inflammation. Int. J. Inflam. 2013, 780502 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Munder, M. et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105, 2549–2556 (2005).

    Article  CAS  PubMed  Google Scholar 

  222. Pesce, J. T. et al. Arginase-1-expressing macrophages suppress TH2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Nair, M. G., Cochrane, D. W. & Allen, J. E. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol. Lett. 85, 173–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  224. Raes, G. et al. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J. Leukoc. Biol. 71, 597–602 (2002).

    CAS  PubMed  Google Scholar 

  225. Durafourt, B. A. et al. Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia 60, 717–727 (2012).

    Article  PubMed  Google Scholar 

  226. Lively, S., Hutchings, S. & Schlichter, L. C. Molecular and cellular responses to interleukin-4 treatment in a rat model of transient ischemia. J. Neuropathol. Exp. Neurol. 75, 1058–1071 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  227. Roberts, A. W. G-CSF: a key regulator of neutrophil production, but that's not all! Growth Factors 23, 33–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  228. Babu, R., Bagley, J. H., Di, C., Friedman, A. H. & Adamson, C. Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg. Focus 32, E8 (2012).

    Article  PubMed  Google Scholar 

  229. Yang, J. et al. Multimodality MRI assessment of grey and white matter injury and blood–brain barrier disruption after intracerebral haemorrhage in mice. Sci. Rep. 7, 40358 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Lei, B. et al. Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage. J. Vis. Exp. 89, 51439 (2014).

    Google Scholar 

  231. Bao, L. et al. Thrombin-induced apoptosis in neurons through activation of c-Jun-N-terminal kinase. Toxicol. Mech. Methods 27, 18–23 (2017).

    Article  CAS  PubMed  Google Scholar 

  232. Hu, S. et al. Thrombin-induced autophagy: a potential role in intracerebral hemorrhage. Brain Res. 1424, 60–66 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Kirkman, M. A., Allan, S. M. & Parry-Jones, A. R. Experimental intracerebral hemorrhage: avoiding pitfalls in translational research. J. Cereb. Blood Flow Metab. 31, 2135–2151 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  234. MacLellan, C. L., Paquette, R. & Colbourne, F. A critical appraisal of experimental intracerebral hemorrhage research. J. Cereb. Blood Flow Metab. 32, 612–627 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Kleinig, T. J. et al. Hemoglobin crystals: a pro-inflammatory potential confounder of rat experimental intracerebral hemorrhage. Brain Res. 1287, 164–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  236. MacLellan, C. L., Davies, L. M., Fingas, M. S. & Colbourne, F. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke 37, 1266–1270 (2006).

    Article  PubMed  Google Scholar 

  237. MacLellan, C. L. et al. Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J. Cereb. Blood Flow Metab. 28, 516–525 (2008).

    Article  CAS  PubMed  Google Scholar 

  238. Manaenko, A., Chen, H., Zhang, J. H. & Tang, J. Comparison of different preclinical models of intracerebral hemorrhage. Acta Neurochir. Suppl. 111, 9–14 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Gong, Y., Hua, Y., Keep, R. F., Hoff, J. T. & Xi, G. Intracerebral hemorrhage: effects of aging on brain edema and neurological deficits. Stroke 35, 2571–2575 (2004).

    Article  PubMed  Google Scholar 

  240. Wasserman, J. K. & Schlichter, L. C. White matter injury in young and aged rats after intracerebral hemorrhage. Exp. Neurol. 214, 266–275 (2008).

    Article  PubMed  Google Scholar 

  241. Lee, J. C., Cho, G. S., Choi, B. O., Kim, H. C. & Kim, W. K. Aging exacerbates intracerebral hemorrhage-induced brain injury. J. Neurotrauma 26, 1567–1576 (2009).

    Article  PubMed  Google Scholar 

  242. Okauchi, M. et al. Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke 41, 375–382 (2010).

    Article  CAS  PubMed  Google Scholar 

  243. MacLellan, C. L., Silasi, G., Auriat, A. M. & Colbourne, F. Rodent models of intracerebral hemorrhage. Stroke 41, S95–S98 (2010).

    Article  PubMed  Google Scholar 

  244. Hiploylee, C. & Colbourne, F. Intracranial pressure measured in freely moving rats for days after intracerebral hemorrhage. Exp. Neurol. 255, 49–55 (2014).

    Article  PubMed  Google Scholar 

  245. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02175225 (2017).

  246. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01805895 (2016).

  247. Kata, D. et al. Rosuvastatin enhances anti-inflammatory and inhibits pro-inflammatory functions in cultured microglial cells. Neuroscience 314, 47–63 (2016).

    Article  CAS  PubMed  Google Scholar 

  248. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00364559 (2009).

  249. Yu, Z. et al. Erythropoietin reduces brain injury after intracerebral hemorrhagic stroke in rats. Mol. Med. Rep. 8, 1315–1322 (2013).

    Article  CAS  PubMed  Google Scholar 

  250. Chau, M., Chen, D. & Wei, L. Erythropoietin attenuates inflammatory factors and cell death in neonatal rats with intracerebral hemorrhage. Acta Neurochir. Suppl. 111, 299–305 (2011).

    Article  PubMed  Google Scholar 

  251. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00413946 (2015).

  252. Lei, C., Wu, B., Cao, T., Liu, M. & Hao, Z. Brain recovery mediated by Toll-like receptor 4 in rats after intracerebral hemorrhage. Brain Res. 1632, 1–8 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors' research work was supported by American Heart Association (AHA) Mid-Atlantic Affiliate Grant-in-Aid 13GRNT15730001, NIH grants R01NS078026 and R01AT007317, and a Stimulating and Advancing ACCM Research (StAAR) grant from the Department of Anesthesiology and Critical Care Medicine (ACCM), Johns Hopkins University (to J.W.), and an AHA Mid-Atlantic Affiliate Postdoctoral Fellowship Award 15POST25090114 (to X.L.). The authors thank Claire Levine, MS, ELS, for assistance with manuscript preparation.

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  1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 370B, Baltimore, 21205, Maryland, USA

    Xi Lan, Xiaoning Han, Qian Li & Jian Wang

  2. Department of Neurology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Main Street, Shapingba District, 400037, Chongqing, China

    Qing-Wu Yang

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  1. Xi Lan
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Contributions

X.L., X.H., and Q.L., researched the data for the article. X.L., Q.-W.Y., and J. W. provided substantial contributions to discussions of the content. X.L. and J.W. wrote and revised the manuscript before submission.

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Correspondence to Jian Wang.

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Lan, X., Han, X., Li, Q. et al. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol 13, 420–433 (2017). https://doi.org/10.1038/nrneurol.2017.69

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