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The Complement Cascade in Acute Brain Injury

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Immunological Mechanisms and Therapies in Brain Injuries and Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR,volume 6))

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Abstract

The prominent role of inflammatory pathways in acute brain injury has become increasingly clear in recent literature. The complement system represents a heterogeneous group of inflammatory molecules capable of being activated by numerous stimuli to a large number of ends. In this chapter, we review the mechanisms of the complement system, with emphasis on C5 and C3. We then present the leading theories of the conflicting role of the complement system in central nervous system disease and the current state of investigations attempting to modify injury through modulation of the complement system.

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References

  1. Miniño AM, et al (2011) Deaths: final data for 2008. In: National Vital Statistics Report. Center for Disease Control and Prevention

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Heidenreich PA et al (2011) Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 123(8):933–44

    PubMed  Google Scholar 

  4. National Heart, Lung, and Blood Institute (2006) Incidence and prevalence: 2006 chart book on cardiovascular and lung diseases. National Institute of Health: National Heart, Lung, and Blood Institute, Bethesda, MD

    Google Scholar 

  5. Roger VL et al (2011) Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123(4):e18–209

    PubMed  Google Scholar 

  6. Bazarian JJ et al (2005) Mild traumatic brain injury in the United States, 1998–2000. Brain Inj 19(2):85–91

    PubMed  Google Scholar 

  7. Carroll LJ et al (2004) Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on mild traumatic brain injury. J Rehabil Med 2004(43 Suppl):84–105

    Google Scholar 

  8. Walport MJ (2001) Complement. First of two parts. N Engl J Med 344(14):1058–66

    CAS  PubMed  Google Scholar 

  9. Cole DS, Morgan BP (2003) Beyond lysis: how complement influences cell fate. Clin Sci (Lond) 104(5):455–66

    CAS  Google Scholar 

  10. Peitsch MC, Tschopp J (1991) Assembly of macromolecular pores by immune defense systems. Curr Opin Cell Biol 3(4):710–6

    CAS  PubMed  Google Scholar 

  11. Lee A, Whyte MK, Haslett C (1993) Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators. J Leukoc Biol 54(4):283–8

    CAS  PubMed  Google Scholar 

  12. Riedemann NC et al (2002) C5a receptor and thymocyte apoptosis in sepsis. FASEB J 16(8):887–8

    CAS  PubMed  Google Scholar 

  13. Takabayashi T et al (1996) A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis. J Immunol 156(9):3455–60

    CAS  PubMed  Google Scholar 

  14. Davis AE 3rd (2004) Biological effects of C1 inhibitor. Drug News Perspect 17(7):439–46

    CAS  PubMed  Google Scholar 

  15. Lampl L et al (1994) Blood coagulation parameters as prognostic factors in multiple trauma: can clinical values be an early diagnostic aid? Zentralbl Chir 119(10):683–9

    CAS  PubMed  Google Scholar 

  16. Lidington EA, Haskard DO, Mason JC (2000) Induction of decay-accelerating factor by thrombin through a protease-activated receptor 1 and protein kinase C-dependent pathway protects vascular endothelial cells from complement-mediated injury. Blood 96(8):2784–92

    CAS  PubMed  Google Scholar 

  17. Ganter MT et al (2007) Role of the alternative pathway in the early complement activation following major trauma. Shock 28(1):29–34

    CAS  PubMed  Google Scholar 

  18. Amara U et al (2008) Interaction between the coagulation and complement system. Adv Exp Med Biol 632:71–9

    CAS  PubMed  Google Scholar 

  19. Huber-Lang M et al (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12(6):682–7

    CAS  PubMed  Google Scholar 

  20. Hankey GJ, Norman PE, Eikelboom JW (2006) Medical treatment of peripheral arterial disease. JAMA 295(5):547–53

    CAS  PubMed  Google Scholar 

  21. Deb P, Sharma S, Hassan KM (2010) Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17(3):197–218

    CAS  PubMed  Google Scholar 

  22. Mocco J et al (2006) The complement system: a potential target for stroke therapy. Adv Exp Med Biol 586:189–201

    CAS  PubMed  Google Scholar 

  23. Feuerstein GZ, Wang X, Barone FC (1998) Cerebrovascular disease: pathophysiology, diagnosis, and management. In: Ginsberg MD, Bogousslavsky J (eds), Blackwell, Malden, MA

    Google Scholar 

  24. Belayev L et al (1996) Quantitative evaluation of blood–brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res 739(1–2):88–96

    CAS  PubMed  Google Scholar 

  25. Klatzo I (1987) Pathophysiological aspects of brain edema. Acta Neuropathol 72(3):236–9

    CAS  PubMed  Google Scholar 

  26. Fishman RA (1992) Cerebrospinal fluid in diseases of the nervous system, 2nd edn. Saunders, Philadelphia, p 431

    Google Scholar 

  27. Adams HP Jr et al (2007) Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 38(5):1655–711

    PubMed  Google Scholar 

  28. Lees KR et al (2010) Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375(9727):1695–703

    CAS  PubMed  Google Scholar 

  29. Fujii Y et al (1994) Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 80(1):51–7

    CAS  PubMed  Google Scholar 

  30. Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5(1):53–63

    PubMed  Google Scholar 

  31. Broderick JP et al (1990) Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg 72(2):195–9

    CAS  PubMed  Google Scholar 

  32. Zazulia AR et al (1999) Progression of mass effect after intracerebral hemorrhage. Stroke 30(6):1167–73

    CAS  PubMed  Google Scholar 

  33. Xi G et al (2001) Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke 32(1):162–7

    CAS  PubMed  Google Scholar 

  34. Hua Y et al (2000) Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg 92(6):1016–22

    CAS  PubMed  Google Scholar 

  35. Hua Y et al (1999) Complement C9 accumulation, membrane attack complex (MAC) formation and cluster in up regulation following intracerebral hemorrhage. J Cereb Blood Flow Metab 19(suppl 1):S670

    Google Scholar 

  36. Zhang X et al (2006) Brain edema after intracerebral hemorrhage in rats: the role of inflammation. Neurol India 54(4):402–7

    PubMed  Google Scholar 

  37. Broderick JP et al (1993) Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 24(7):987–93

    CAS  PubMed  Google Scholar 

  38. Broderick J et al (2007) Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation 116(16):e391–413

    PubMed  Google Scholar 

  39. Ropper AH (1986) Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med 314(15):953–8

    CAS  PubMed  Google Scholar 

  40. Ropper AH, King RB (1984) Intracranial pressure monitoring in comatose patients with cerebral hemorrhage. Arch Neurol 41(7):725–8

    CAS  PubMed  Google Scholar 

  41. Morgenstern LB et al (2010) Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41(9):2108–29

    PubMed  Google Scholar 

  42. Sughrue ME et al (2004) Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: a critical review of the literature. Inflamm Res 53(10):497–508

    CAS  PubMed  Google Scholar 

  43. Schafer MK et al (2000) Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. J Immunol 164(10):5446–52

    CAS  PubMed  Google Scholar 

  44. Cowell RM, Plane JM, Silverstein FS (2003) Complement activation contributes to hypoxic-ischemic brain injury in neonatal rats. J Neurosci 23(28):9459–68

    PubMed  Google Scholar 

  45. Huang J et al (1999) Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 285(5427):595–9

    CAS  PubMed  Google Scholar 

  46. Rahpeymai Y et al (2006) Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J 25(6):1364–74

    CAS  PubMed  Google Scholar 

  47. Gasque P et al (2000) Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49(1–2):171–86

    CAS  PubMed  Google Scholar 

  48. Nataf S, Levison SW, Barnum SR (2001) Expression of the anaphylatoxin C5a receptor in the oligodendrocyte lineage. Brain Res 894(2):321–6

    CAS  PubMed  Google Scholar 

  49. Spiegel K, Emmerling M, Barnum S (1998) Strategies for inhibition of complement activation in the treatment of neurodegenerative diseases. In: Wood PL (ed) Neuroinflammation: mechanisms and management. Humana, Totowa, NJ, p 375

    Google Scholar 

  50. Thomas A et al (2000) Expression of a complete and functional complement system by human neuronal cells in vitro. Int Immunol 12(7):1015–23

    CAS  PubMed  Google Scholar 

  51. D’Ambrosio AL, Pinsky DJ, Connolly ES (2001) The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med 7(6):367–82

    PubMed  Google Scholar 

  52. Gasque P et al (1993) Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells. J Biol Chem 268(33):25068–74

    CAS  PubMed  Google Scholar 

  53. Gasque P et al (1992) Expression of complement components of the alternative pathway by glioma cell lines. J Immunol 149(4):1381–7

    CAS  PubMed  Google Scholar 

  54. van Beek J, Elward K, Gasque P (2003) Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci 992:56–71

    PubMed  Google Scholar 

  55. Thrane AS, Skehan JD, Thrane PS (2007) A novel interpretation of immune redundancy and duality in reperfusion injury with important implications for intervention in ischaemic disease. Med Hypotheses 68(6):1363–70

    CAS  PubMed  Google Scholar 

  56. Ducruet AF et al (2011) The neuroprotective effect of genetic mannose-binding lectin deficiency is not sustained in the sub-acute phase of stroke. Transl Stroke Res 2(4):588–99

    CAS  PubMed  Google Scholar 

  57. Yano T et al (2003) Neuroprotective effect of urinary trypsin inhibitor against focal cerebral ischemia–reperfusion injury in rats. Anesthesiology 98(2):465–73

    CAS  PubMed  Google Scholar 

  58. Shimakura A et al (2000) Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion. Brain Res 858(1):55–60

    CAS  PubMed  Google Scholar 

  59. Qureshi AI et al (2001) Spontaneous intracerebral hemorrhage. N Engl J Med 344(19):1450–60

    CAS  PubMed  Google Scholar 

  60. Xi G et al (2001) Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood–brain barrier integrity. Stroke 32(12):2932–8

    CAS  PubMed  Google Scholar 

  61. Clark A et al (2008) Evidence for non-traditional activation of complement factor C3 during murine liver regeneration. Mol Immunol 45(11):3125–32

    CAS  PubMed  Google Scholar 

  62. Gong Y et al (2005) Complement inhibition attenuates brain edema and neurological deficits induced by thrombin. Acta Neurochir Suppl 95:389–92

    CAS  PubMed  Google Scholar 

  63. Kitaoka T et al (2002) Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage. Stroke 33(12):3012–8

    CAS  PubMed  Google Scholar 

  64. Matsuoka H, Hamada R (2002) Role of thrombin in CNS damage associated with intracerebral haemorrhage: opportunity for pharmacological intervention? CNS Drugs 16(8):509–16

    CAS  PubMed  Google Scholar 

  65. Hua Y et al (2007) Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke 38(2 Suppl):759–62

    CAS  PubMed  Google Scholar 

  66. Rynkowski MA et al (2009) C3a receptor antagonist attenuates brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab 29(1):98–107

    CAS  PubMed  Google Scholar 

  67. Lucchesi BR (1993) Complement activation, neutrophils, and oxygen radicals in reperfusion injury. Stroke 24(12):I41–7

    CAS  PubMed  Google Scholar 

  68. Xi G et al (2002) Brain edema after intracerebral hemorrhage: the effects of systemic complement depletion. Acta Neurochir Suppl 81:253–6

    CAS  PubMed  Google Scholar 

  69. Aronowski J, Hall CE (2005) New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 27(3):268–79

    PubMed  Google Scholar 

  70. Okusawa S et al (1988) C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha. J Exp Med 168(1):443–8

    CAS  PubMed  Google Scholar 

  71. Lee KR et al (1997) Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood–brain barrier permeability, and cell survival in a rat model. J Neurosurg 86(2):272–8

    CAS  PubMed  Google Scholar 

  72. Muller-Eberhard HJ (1986) The membrane attack complex of complement. Annu Rev Immunol 4:503–28

    CAS  PubMed  Google Scholar 

  73. Wu J et al (2003) Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 34(12):2964–9

    CAS  PubMed  Google Scholar 

  74. Xi G, Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89(6):991–6

    CAS  PubMed  Google Scholar 

  75. Wang X et al (2002) Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33(7):1882–8

    CAS  PubMed  Google Scholar 

  76. Wagner KR et al (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23(6):629–52

    CAS  PubMed  Google Scholar 

  77. Gasque P et al (1998) The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis. J Immunol 160(7):3543–54

    CAS  PubMed  Google Scholar 

  78. Head E et al (2001) Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down syndrome. Neurobiol Dis 8(2):252–65

    CAS  PubMed  Google Scholar 

  79. Matsuoka Y et al (2001) Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 158(4):1345–54

    CAS  PubMed  Google Scholar 

  80. Eikelenboom P et al (1989) Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Arch B Cell Pathol Incl Mol Pathol 56(4):259–62

    CAS  PubMed  Google Scholar 

  81. McGeer PL et al (1989) Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107(1–3):341–6

    CAS  PubMed  Google Scholar 

  82. Yasuhara O et al (1994) Expression of the complement membrane attack complex and its inhibitors in Pick disease brain. Brain Res 652(2):346–9

    CAS  PubMed  Google Scholar 

  83. Singhrao SK et al (1996) Role of complement in the aetiology of Pick’s disease? J Neuropathol Exp Neurol 55(5):578–93

    CAS  PubMed  Google Scholar 

  84. Kasuya H, Shimizu T (1989) Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage. J Neurosurg 71(5 Pt 1):741–6

    CAS  PubMed  Google Scholar 

  85. Mack WJ et al (2007) Early plasma complement C3a levels correlate with functional outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery 61(2):255–60, discussion 260-1

    PubMed  Google Scholar 

  86. Yates JR et al (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357(6):553–61

    CAS  PubMed  Google Scholar 

  87. Rancan M et al (2003) Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. J Cereb Blood Flow Metab 23(9):1070–4

    CAS  PubMed  Google Scholar 

  88. Bellander BM et al (2001) Complement activation in the human brain after traumatic head injury. J Neurotrauma 18(12):1295–311

    CAS  PubMed  Google Scholar 

  89. Kaczorowski SL et al (1995) Effect of soluble complement receptor-1 on neutrophil accumulation after traumatic brain injury in rats. J Cereb Blood Flow Metab 15(5):860–4

    CAS  PubMed  Google Scholar 

  90. Keeling KL et al (2000) Local neutrophil influx following lateral fluid-percussion brain injury in rats is associated with accumulation of complement activation fragments of the third component (C3) of the complement system. J Neuroimmunol 105(1):20–30

    CAS  PubMed  Google Scholar 

  91. Morganti-Kossmann M-C et al (2002) Inflammatory responses to traumatic brain injury: an overview for the new millennium. In: Rothwwell N, Lodick S (eds) Immune and inflammatory responses in the nervous system. Oxford University Press, Oxford, UK

    Google Scholar 

  92. Nataf S et al (1999) Complement anaphylatoxin receptors on neurons: new tricks for old receptors? Trends Neurosci 22(9):397–402

    CAS  PubMed  Google Scholar 

  93. Stahel PF, Morganti-Kossmann MC, Kossmann T (1998) The role of the complement system in traumatic brain injury. Brain Res Brain Res Rev 27(3):243–56

    CAS  PubMed  Google Scholar 

  94. Stahel PF et al (2001) Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood–brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma 18(8):773–81

    CAS  PubMed  Google Scholar 

  95. Gasque P et al (1996) Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. J Neuroimmunol 66(1–2):29–40

    CAS  PubMed  Google Scholar 

  96. Singhrao SK et al (2000) Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol 157(3):905–18

    CAS  PubMed  Google Scholar 

  97. Figueroa E et al (2005) The administration of cobra venom factor reduces post-ischemic cerebral injury in adult and neonatal rats. Neurosci Lett 380(1–2):48–53

    CAS  PubMed  Google Scholar 

  98. Vasthare US et al (1998) Complement depletion improves neurological function in cerebral ischemia. Brain Res Bull 45(4):413–9

    CAS  PubMed  Google Scholar 

  99. Akita N et al (2001) The effect of C 1 esterase inhibitor on ischemia: reperfusion injury in the rat brain. No To Shinkei 53(7):641–4

    CAS  PubMed  Google Scholar 

  100. De Simoni MG et al (2003) Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab 23(2):232–9

    PubMed  Google Scholar 

  101. De Simoni MG et al (2004) The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol 164(5):1857–63

    PubMed  Google Scholar 

  102. Weisman HF et al (1990) Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249(4965):146–51

    CAS  PubMed  Google Scholar 

  103. Mocco J et al (2006) Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke. J Neurosurg 105(4):595–601

    CAS  PubMed  Google Scholar 

  104. Ducruet AF et al (2007) Pre-clinical evaluation of an sLe x-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke. J Med Primatol 36(6):375–80

    CAS  PubMed  Google Scholar 

  105. Kilgore KS et al (1998) Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischemia/reperfusion. J Mol Cell Cardiol 30(1):75–85

    CAS  PubMed  Google Scholar 

  106. Mack WJ et al (2006) Temporal pattern of C1q deposition after transient focal cerebral ischemia. J Neurosci Res 83(5):883–9

    CAS  PubMed  Google Scholar 

  107. Mocco J et al (2006) Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circ Res 99(2):209–17

    CAS  PubMed  Google Scholar 

  108. Mocco J et al (2006) Alterations in plasma complement levels after human ischemic stroke. Neurosurgery 59(1):28–33, discussion 28–33

    CAS  PubMed  Google Scholar 

  109. Furuya K et al (2001) Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke 32(11):2665–74

    CAS  PubMed  Google Scholar 

  110. Vuorte J et al (1999) Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood. J Immunol 162(4):2353–7

    CAS  PubMed  Google Scholar 

  111. Pedersen ED et al (2009) In situ deposition of complement in human acute brain ischaemia. Scand J Immunol 69(6):555–62

    CAS  PubMed  Google Scholar 

  112. Xi G, Keep RF, Hoff JT (2002) Pathophysiology of brain edema formation. Neurosurg Clin N Am 13(3):371–83

    PubMed  Google Scholar 

  113. Wu G, Huang FP (2005) Effects of venom defibrase on brain edema after intracerebral hemorrhage in rats. Acta Neurochir Suppl 95:381–7

    CAS  PubMed  Google Scholar 

  114. Nakamura T et al (2004) Intracerebral hemorrhage in mice: model characterization and application for genetically modified mice. J Cereb Blood Flow Metab 24(5):487–94

    PubMed  Google Scholar 

  115. Mukherjee P, Pasinetti GM (2000) The role of complement anaphylatoxin C5a in neurodegeneration: implications in Alzheimer’s disease. J Neuroimmunol 105(2):124–30

    CAS  PubMed  Google Scholar 

  116. Ducruet AF et al (2008) C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent. J Cereb Blood Flow Metab 28(5):1048–58

    CAS  PubMed  Google Scholar 

  117. Yang S et al (2006) The role of complement C3 in intracerebral hemorrhage-induced brain injury. J Cereb Blood Flow Metab 26(12):1490–5

    CAS  PubMed  Google Scholar 

  118. Yang S et al (2006) Intracerebral hemorrhage in complement C3-deficient mice. Acta Neurochir Suppl 96:227–31

    CAS  PubMed  Google Scholar 

  119. Rynkowski MA et al (2008) A mouse model of intracerebral hemorrhage using autologous blood infusion. Nat Protoc 3(1):122–8

    CAS  PubMed  Google Scholar 

  120. Garrett MC et al (2009) Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res 1298:171–7

    CAS  PubMed  Google Scholar 

  121. Mevorach D (1999) The immune response to apoptotic cells. Ann N Y Acad Sci 887:191–8

    CAS  PubMed  Google Scholar 

  122. Mevorach D (2000) Opsonization of apoptotic cells. Implications for uptake and autoimmunity. Ann N Y Acad Sci 926:226–35

    CAS  PubMed  Google Scholar 

  123. Mevorach D (2003) Systemic lupus erythematosus and apoptosis: a question of balance. Clin Rev Allergy Immunol 25(1):49–60

    CAS  PubMed  Google Scholar 

  124. Mevorach D et al (1998) Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med 188(12):2313–20

    CAS  PubMed  Google Scholar 

  125. Fishelson Z, Attali G, Mevorach D (2001) Complement and apoptosis. Mol Immunol 38(2–3):207–19

    CAS  PubMed  Google Scholar 

  126. Wyss-Coray T et al (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci USA 99(16):10837–42

    CAS  PubMed  Google Scholar 

  127. Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407(6805):784–8

    CAS  PubMed  Google Scholar 

  128. Fadok VA (1999) Clearance: the last and often forgotten stage of apoptosis. J Mammary Gland Biol Neoplasia 4(2):203–11

    CAS  PubMed  Google Scholar 

  129. Fadok VA et al (1998) The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 5(7):551–62

    CAS  PubMed  Google Scholar 

  130. Fadok VA, Henson PM (1998) Apoptosis: getting rid of the bodies. Curr Biol 8(19):R693–5

    CAS  PubMed  Google Scholar 

  131. Fadok VA et al (1998) CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3). J Immunol 161(11):6250–7

    CAS  PubMed  Google Scholar 

  132. Elward K, Gasque P (2003) “Eat me” and “don’t eat me” signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system. Mol Immunol 40(2–4):85–94

    CAS  PubMed  Google Scholar 

  133. Savill J (2000) Apoptosis in resolution of inflammation. Kidney Blood Press Res 23(3–5):173–4

    CAS  PubMed  Google Scholar 

  134. Fadok VA, Chimini G (2001) The phagocytosis of apoptotic cells. Semin Immunol 13(6):365–72

    CAS  PubMed  Google Scholar 

  135. Savill J (1997) Apoptosis in resolution of inflammation. J Leukoc Biol 61(4):375–80

    CAS  PubMed  Google Scholar 

  136. De Simone R et al (2003) Apoptotic PC12 cells exposing phosphatidylserine promote the production of anti-inflammatory and neuroprotective molecules by microglial cells. J Neuropathol Exp Neurol 62(2):208–16

    PubMed  Google Scholar 

  137. Strey CW et al (2003) The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med 198(6):913–23

    CAS  PubMed  Google Scholar 

  138. Markiewski MM et al (2004) C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. J Immunol 173(2):747–54

    CAS  PubMed  Google Scholar 

  139. DeAngelis RA, Markiewski MM, Lambris JD (2006) Liver regeneration: a link to inflammation through complement. Adv Exp Med Biol 586:17–34

    CAS  PubMed  Google Scholar 

  140. Shen J et al (2008) Neurogenesis after primary intracerebral hemorrhage in adult human brain. J Cereb Blood Flow Metab 28(8):1460–8

    PubMed  Google Scholar 

  141. Yang S et al (2008) Effects of thrombin on neurogenesis after intracerebral hemorrhage. Stroke 39(7):2079–84

    CAS  PubMed  Google Scholar 

  142. Bogestal YR et al (2007) Signaling through C5aR is not involved in basal neurogenesis. J Neurosci Res 85(13):2892–7

    PubMed  Google Scholar 

  143. Moriyama M et al (2011) Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis. J Neurosci 31(11):3981–9

    CAS  PubMed  Google Scholar 

  144. Ducruet AF et al (2012) Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS One 7(6):e38664

    CAS  PubMed  Google Scholar 

  145. Arumugam TV et al (2009) Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience 158(3):1074–89

    CAS  PubMed  Google Scholar 

  146. Hughes RA, Cornblath DR (2005) Guillain–Barre syndrome. Lancet 366(9497):1653–66

    CAS  PubMed  Google Scholar 

  147. Archelos JJ, Fazekas F (2006) IVIG therapy in neurological disorders of childhood. J Neurol 253(Suppl 5):V80–6

    PubMed  Google Scholar 

  148. Ringel I, Zettl UK (2006) Intravenous immunoglobulin therapy in neurological diseases during pregnancy. J Neurol 253(Suppl 5):V70–4

    PubMed  Google Scholar 

  149. Stangel M, Pul R (2006) Basic principles of intravenous immunoglobulin (IVIg) treatment. J Neurol 253(Suppl 5):V18–24

    PubMed  Google Scholar 

  150. Arumugam TV et al (2007) Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proc Natl Acad Sci USA 104(35):14104–9

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Columbia University Medical Center, New York, NY, USA

    Michael McDowell, Nicholas Shea, Gaurav Gupta & E. Sander Connolly Jr.

Authors
  1. Michael McDowell
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  2. Nicholas Shea
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  3. Gaurav Gupta
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  4. E. Sander Connolly Jr.
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Correspondence to E. Sander Connolly Jr. .

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Editors and Affiliations

  1. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Jun Chen

  2. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Xiaoming Hu

  3. Molecular Microbiology & Immunology, Oregon Health & Sciences University, Portland, Oregon, USA

    Mary Stenzel-Poore

  4. Loma Linda University, Loma Linda, California, USA

    John H. Zhang

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McDowell, M., Shea, N., Gupta, G., Connolly, E.S. (2014). The Complement Cascade in Acute Brain Injury. In: Chen, J., Hu, X., Stenzel-Poore, M., Zhang, J. (eds) Immunological Mechanisms and Therapies in Brain Injuries and Stroke. Springer Series in Translational Stroke Research, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8915-3_5

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  • DOI: https://doi.org/10.1007/978-1-4614-8915-3_5

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