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Microglial Function in Intracerebral Hemorrhage Injury and Recovery

  • A-Hyun Cho
  • Neethu Michael
  • David H. Cribbs
  • Mark J. FisherEmail author
Chapter
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Part of the Springer Series in Translational Stroke Research book series (SSTSR)

Abstract

Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes and is a major cause of disability and mortality. Introduction of blood components (e.g., thrombin, heme, and platelets) following ICH initiates neuroinflammatory responses mainly mediated by microglia, which are the resident immune cells in the central nervous system. Microglia have been shown to have dual roles in ICH, both beneficial and detrimental. The beneficial role involves phagocytosis of cellular debris and red blood cells after the hemorrhagic incident, while the detrimental role involves the production of pro-inflammatory cytokines and chemokines resulting in neuroinflammation. These dual and contradictory roles of microglia are thought to be implemented by two distinct phenotypes: classically-activated microglia and alternatively-activated microglia. We discuss herein the role of microglia in ICH with particular emphasis on its role in brain injury and recovery after ICH.

Keywords

Microglia Intracerebral hemorrhage Brain injury Brain recovery Neuroinflammation 

Abbreviations

BBB

Blood-brain barrier

Bcl-2

B-cell lymphoma-2

Bcl-xl

B-cell lymphoma-extra large

CD36

Cluster of differentiation 36

CD47

Cluster of differentiation 47

CEBP α

CCAAT/enhancer-binding protein alpha

CNS

Central nervous system

CX3CR-1

CX3C chemokine receptor-1

CXCL2

Chemokine (C-X-C motif) ligand 2

HO

Heme oxygenase

ICH

Intracerebral hemorrhage

IL

Interleukin

KO

Knock-out

MHCII

Major histocompatibility complex II

mTOR

Mechanistic target of rapamycin

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

Nrf2

Nuclear factor (erythroid-derived 2)-like 2

PAR-1

Protease activated receptor-1

PI3K

Phosphoinositide 3-kinase

PPAR-γ

Peroxisome proliferator-activated receptor gamma

ROS

Reactive oxygen species

SIRPα

Signal-regulatory protein α

TGF-β1

Transforming growth factor-beta 1

TLR

Toll-like receptors

TNF-α

Tumor necrosis factor-α

Notes

Acknowledgement

This work is supported by NIH R01 NS20989

References

  1. 1.
    Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373(9675):1632–44.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Qureshi AI, Suri MF, Nasar A, Kirmani JF, Ezzeddine MA, Divani AA, et al. Changes in cost and outcome among US patients with stroke hospitalized in 1990 to 1991 and those hospitalized in 2000 to 2001. Stroke. 2007;38(7):2180–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Egashira Y, Hua Y, Keep RF, Xi G. Intercellular cross-talk in intracerebral hemorrhage. Brain Res. 2015;1623:97–109.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol. 2015;11(1):56–64.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang J, Tsirka SE. Contribution of extracellular proteolysis and microglia to intracerebral hemorrhage. Neurocrit Care. 2005;3(1):77–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Wang J, Rogove AD, Tsirka AE, Tsirka SE. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol. 2003;54(5):655–64.CrossRefPubMedGoogle Scholar
  7. 7.
    Askenase MH, Sansing LH. Stages of the inflammatory response in pathology and tissue repair after intracerebral hemorrhage. Semin Neurol. 2016;36(3):288–97.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Hammond MD, Taylor RA, Mullen MT, Ai Y, Aguila HL, Mack M, et al. CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci. 2014;34(11):3901–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang Z, Zhang Z, Lu H, Yang Q, Wu H, Wang J. Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage. Mol Neurobiol. 2017;54(3):1874–86.CrossRefPubMedGoogle Scholar
  12. 12.
    Starossom SC, Mascanfroni ID, Imitola J, Cao L, Raddassi K, Hernandez SF, et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012;37(2):249–63.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol. 2013;2013:746068.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lin S, Yin Q, Zhong Q, Lv FL, Zhou Y, Li JQ, et al. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflammation. 2012;9:46.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang YC, Wang PF, Fang H, Chen J, Xiong XY, Yang QW. Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury. Stroke. 2013;44(9):2545–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Yang Z, Liu B, Zhong L, Shen H, Lin C, Lin L, et al. Toll-like receptor-4-mediated autophagy contributes to microglial activation and inflammatory injury in mouse models of intracerebral haemorrhage. Neuropathol Appl Neurobiol. 2015;41(4):e95–106.CrossRefPubMedGoogle Scholar
  17. 17.
    Wan S, Cheng Y, Jin H, Guo D, Hua Y, Keep RF, et al. Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1. Transl Stroke Res. 2016;7(6):478–87.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang J, Doré S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain : a journal of neurology. 2007;130(Pt 6):1643–1652.Google Scholar
  19. 19.
    Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5(11):863–73.CrossRefPubMedGoogle Scholar
  20. 20.
    Yu A, Zhang T, Zhong W, Duan H, Wang S, Ye P, et al. miRNA-144 induces microglial autophagy and inflammation following intracerebral hemorrhage. Immunol Lett. 2017;182:18–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Shiratori M, Tozaki-Saitoh H, Yoshitake M, Tsuda M, Inoue K. P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways. J Neurochem. 2010;114(3):810–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci. 2016;19(8):987–91.CrossRefPubMedGoogle Scholar
  23. 23.
    Yang J, Ding S, Huang W, Hu J, Huang S, Zhang Y, et al. Interleukin-4 ameliorates the functional recovery of intracerebral hemorrhage through the alternative activation of microglia/macrophage. Front Neurosci. 2016;10:61.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu X, Liu J, Zhao S, Zhang H, Cai W, Cai M, et al. Interleukin-4 is essential for microglia/macrophage M2 polarization and long-term recovery after cerebral ischemia. Stroke. 2016;47(2):498–504.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43(11):3063–70.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Bisht K, Sharma KP, Lecours C, Sanchez MG, El Hajj H, Milior G, et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia. 2016;64(5):826–39.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10(11):1387–94.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol. 2007;61(4):352–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Zamora C, Canto E, Nieto JC, Angels Ortiz M, Juarez C, Vidal S. Functional consequences of CD36 downregulation by TLR signals. Cytokine. 2012;60(1):257–65.CrossRefPubMedGoogle Scholar
  31. 31.
    Fang H, Chen J, Lin S, Wang P, Wang Y, Xiong X, et al. CD36-mediated hematoma absorption following intracerebral hemorrhage: negative regulation by TLR4 signaling. J Immunol. 2014;192(12):5984–92.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rodriguez-Yanez M, Brea D, Arias S, Blanco M, Pumar JM, Castillo J, et al. Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage. J Neuroimmunol. 2012;247(1-2):75–80.CrossRefPubMedGoogle Scholar
  34. 34.
    Ni W, Mao S, Xi G, Keep RF, Hua Y. Role of erythrocyte CD47 in intracerebral hematoma clearance. Stroke. 2016;47(2):505–11.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Masuda T, Isobe Y, Aihara N, Furuyama F, Misumi S, Kim TS, et al. Increase in neurogenesis and neuroblast migration after a small intracerebral hemorrhage in rats. Neurosci Lett. 2007;425(2):114–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Shen J, Xie L, Mao X, Zhou Y, Zhan R, Greenberg DA, et al. Neurogenesis after primary intracerebral hemorrhage in adult human brain. J Cereb Blood Flow Metab. 2008;28(8):1460–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632–7.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149–60.CrossRefPubMedGoogle Scholar
  39. 39.
    Kim BJ, Kim MJ, Park JM, Lee SH, Kim YJ, Ryu S, et al. Reduced neurogenesis after suppressed inflammation by minocycline in transient cerebral ischemia in rat. J Neurol Sci. 2009;279(1-2):70–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Nikolakopoulou AM, Dutta R, Chen Z, Miller RH, Trapp BD. Activated microglia enhance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci U S A. 2013;110(21):8714–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yan YP, Lang BT, Vemuganti R, Dempsey RJ. Galectin-3 mediates post-ischemic tissue remodeling. Brain Res. 2009;1288:116–24.CrossRefPubMedGoogle Scholar
  42. 42.
    Choi YS, Cho HY, Hoyt KR, Naegele JR, Obrietan K. IGF-1 receptor-mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus. Glia. 2008;56(7):791–800.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kitayama M, Ueno M, Itakura T, Yamashita T. Activated microglia inhibit axonal growth through RGMa. PLoS One. 2011;6(9):e25234.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Horn KP, Busch SA, Hawthorne AL, van Rooijen N, Silver J. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J Neurosci. 2008;28(38):9330–41.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 2009;6(7):e1000113.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tang T, Liu XJ, Zhang ZQ, Zhou HJ, Luo JK, Huang JF, et al. Cerebral angiogenesis after collagenase-induced intracerebral hemorrhage in rats. Brain Res. 2007;1175:134–42.CrossRefPubMedGoogle Scholar
  47. 47.
    Zajac E, Schweighofer B, Kupriyanova TA, Juncker-Jensen A, Minder P, Quigley JP, et al. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood. 2013;122(25):4054–67.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Medina RJ, O’Neill CL, O’Doherty TM, Knott H, Guduric-Fuchs J, Gardiner TA, et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol Med. 2011;17(9-10):1045–55.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120(3):613–25.CrossRefPubMedGoogle Scholar
  50. 50.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013;16(9):1211–8.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW, et al. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med. 2007;43(3):408–14.Google Scholar
  54. 54.
    Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J. 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-gamma, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab. 2006;26(6):811–20.CrossRefPubMedGoogle Scholar
  55. 55.
    Yu A, Zhang T, Duan H, Pan Y, Zhang X, Yang G, et al. MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-alpha pathway in intracerebral hemorrhage. Immunol Lett. 2017;182:1–11.CrossRefPubMedGoogle Scholar
  56. 56.
    Ponomarev ED, Maresz K, Tan Y, Dittel BN. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci. 2007;27(40):10714–21.CrossRefPubMedGoogle Scholar
  57. 57.
    Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.CrossRefPubMedGoogle Scholar
  58. 58.
    Taylor RA, Chang CF, Goods BA, Hammond MD, Mac Grory B, Ai Y, et al. TGF-beta1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J Clin Invest. 2017;127(1):280–92.CrossRefPubMedGoogle Scholar
  59. 59.
    Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, et al. Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3beta/PTEN axis. J Cereb Blood Flow Metab. 2017;37(3):967–79.CrossRefPubMedGoogle Scholar
  60. 60.
    Yang Y, Liu H, Zhang H, Ye Q, Wang J, Yang B, et al. ST2/IL-33-dependent microglial response limits acute ischemic brain injury. J Neurosci. 2017;37(18):4692–704.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia. 2013;61(1):10–23.CrossRefPubMedGoogle Scholar
  62. 62.
    Flogel U, Ding Z, Hardung H, Jander S, Reichmann G, Jacoby C, et al. In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging. Circulation. 2008;118(2):140–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • A-Hyun Cho
    • 1
    • 2
  • Neethu Michael
    • 2
  • David H. Cribbs
    • 3
  • Mark J. Fisher
    • 2
    • 4
    • 5
    • 6
    Email author
  1. 1.Department of NeurologyYeoudio St. Mary’s Hospital, Catholic University of KoreaSeoulSouth Korea
  2. 2.Department of NeurologyUniversity of CaliforniaIrvineUSA
  3. 3.UCI MINDUniversity of CaliforniaIrvineUSA
  4. 4.Department of Anatomy & NeurobiologyUniversity of CaliforniaIrvineUSA
  5. 5.Department of Pathology & Laboratory MedicineUniversity of CaliforniaIrvineUSA
  6. 6.Department of NeurologyUC Irvine Medical CenterOrangeUSA

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