Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Review

Complement activation in the injured central nervous system: another dual-edged sword?

Authors: Faith H Brennan, Aileen J Anderson, Stephen M Taylor, Trent M Woodruff, Marc J Ruitenberg

Published in: Journal of Neuroinflammation | Issue 1/2012

Login to get access

Abstract

The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS) function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions.
Literature
1.
Taoka Y, Okajima K, Uchiba M, Murakami K, Kushimoto S, Johno M, Naruo M, Okabe H, Takatsuki K: Role of neutrophils in spinal cord injury in the rat. Neuroscience 1997, 79:1177–1182.PubMedCrossRef
2.
Gris D, Marsh DR, Oatway MA, Chen Y, Hamilton EF, Dekaban GA, Weaver LC: Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci 2004, 24:4043–4051.PubMedCrossRef
3.
Stirling DP, Liu S, Kubes P, Yong VW: Depletion of Ly6G/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome. J Neurosci 2009, 29:753–764.PubMedCrossRef
4.
Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ: Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 2010, 133:433–447.PubMedPubMedCentralCrossRef
5.
Geremia NM, Bao F, Rosenzweig TE, Hryciw T, Weaver L, Dekaban GA, Brown A: CD11d antibody treatment improves recovery in spinal cord-injured mice. J Neurotrauma 2012, 29:539–550.PubMedCrossRef
6.
Popovich P, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes B: Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 1999, 158:351–365.PubMedCrossRef
7.
Mabon PJ, Weaver LC, Dekaban GA: Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin alphaD: a potential new anti-inflammatory treatment. Exp Neurol 2000, 166:52–64.PubMedCrossRef
8.
Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M: Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 2009, 6:e1000113.PubMedPubMedCentralCrossRef
9.
Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG: Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009, 29:13435–13444.PubMedPubMedCentralCrossRef
10.
Popovich PG, Stokes BT, Whitacre CC: Concept of autoimmunity following spinal cord injury: possible roles for T lymphocytes in the traumatized central nervous system. J Neurosci Res 1996, 45:349–363.PubMedCrossRef
11.
Schwartz M, Hauben E: T cell-based therapeutic vaccination for spinal cord injury. Prog Brain Res 2002, 137:401–406.PubMedCrossRef
12.
Ankeny DP, Guan Z, Popovich PG: B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. J Clin Invest 2009, 119:2990–2999.PubMedPubMedCentralCrossRef
13.
14.
Anderson A, Robert S, Huang W, Young W, Cotman C: Activation of complement pathways after contusion-induced spinal cord injury. J Neurotrauma 2004, 21:1831–1846.PubMedCrossRef
15.
Nguyen H, Galvan M, Anderson A: Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury. J Neuroinflammation 2008, 5:26.PubMedPubMedCentralCrossRef
16.
Qiao F, Atkinson C, Kindy MS, Shunmugavel A, Morgan BP, Song H, Tomlinson S: The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury. Am J Pathol 2010, 177:3061–3070.PubMedPubMedCentralCrossRef
17.
Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Fang S, Parsa AT: Complement and the central nervous system: emerging roles in development, protection and regeneration. Immunol Cell Biol 2010, 88:781–786.PubMedCrossRef
18.
Woodruff TM, Ager RR, Tenner AJ, Noakes PG, Taylor SM: The role of the complement system and the activation fragment C5a in the central nervous system. Neuromolecular Med 2010, 12:179–192.PubMedCrossRef
19.
20.
Alper CA, Johnson AM, Birtch AG, Moore FD: Human C'3: evidence for the liver as the primary site of synthesis. Science 1969, 163:286–288.PubMedCrossRef
21.
Gaboriaud C, Thielens NM, Gregory LA, Rossi V, Fontecilla-Camps JC, Arlaud GJ: Structure and activation of the C1 complex of complement: unraveling the puzzle. Trends Immunol 2004, 25:368–373.PubMedCrossRef
22.
Carroll MC: The complement system in regulation of adaptive immunity. Nat Immunol 2004, 5:981–986.PubMedCrossRef
23.
Holers VM, Kulik L: Complement receptor 2, natural antibodies and innate immunity: Inter-relationships in B cell selection and activation. Mol Immunol 2007, 44:64–72.PubMedCrossRef
24.
25.
26.
Kwan WH, van der Touw W, Heeger PS: Complement regulation of T cell immunity. Immunol Res 2012,:. Epub ahead of print
27.
Stahl PD, Ezekowitz RA: The mannose receptor is a pattern recognition receptor involved in host defense. Curr Opin Immunol 1998, 10:50–55.PubMedCrossRef
28.
29.
Pangburn MK, Schreiber RD, Muller-Eberhard HJ: Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3. J Exp Med 1981, 154:856–67.PubMedCrossRef
30.
Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007, 81:1–5.PubMedCrossRef
31.
32.
Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA: Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006, 12:682–687.PubMedCrossRef
33.
Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M: Molecular intercommunication between the complement and coagulation systems. J Immunol 2010, 185:5628–5636.PubMedPubMedCentralCrossRef
34.
Perl M, Denk S, Kalbitz M, Huber-Lang M: Granzyme B: a new crossroad of complement and apoptosis. Adv Exp Med Biol 2012, 946:135–146.PubMedCrossRef
35.
Ames RS, Li Y, Sarau HM, Nuthulaganti P, Foley JJ, Ellis C, Zeng Z, Su K, Jurewicz AJ, Hertzberg RP, Bergsma DJ, Kumar C: Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J Biol Chem 1996, 271:20231–20234.PubMedCrossRef
36.
Manthey HD, Woodruff TM, Taylor SM, Monk PN: Complement component 5a (C5a). Int J Biochem Cell Biol 2009, 41:2114–2117.PubMedCrossRef
37.
Gerard NP, Gerard C: The chemotactic receptor for human C5a anaphylatoxin. Nature 1991, 349:614–617.PubMedCrossRef
38.
Cain SA, Monk PN: The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). J Biol Chem 2002, 277:7165–7169.PubMedCrossRef
39.
Chen NJ, Mirtsos C, Suh D, Lu YC, Lin WJ, McKerlie C, Lee T, Baribault H, Tian H, Yeh WC: C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 2007, 446:203–207.PubMedCrossRef
40.
Scola AM, Johswich KO, Morgan BP, Klos A, Monk PN: The human complement fragment receptor, C5L2, is a recycling decoy receptor. Mol Immunol 2009, 46:1149–1162.PubMedPubMedCentralCrossRef
41.
Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Kohl J, Gerard C, Sarma JV, Ward PA: Functional roles for C5a receptors in sepsis. Nat Med 2008, 14:551–557.PubMedPubMedCentralCrossRef
42.
Bamberg CE, Mackay CR, Lee H, Zahra D, Jackson J, Lim YS, Whitfeld PL, Craig S, Corsini E, Lu B, Gerard C, Gerard NP: The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. J Biol Chem 2010, 285:7633–7644.PubMedCrossRef
43.
Perry VH, O'Connor V: C1q: the perfect complement for a synaptic feast? Nat Rev Neurosci 2008, 9:807–811.PubMedCrossRef
44.
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA: The classical complement cascade mediates CNS synapse elimination. Cell 2007, 131:1164–1178.PubMedCrossRef
45.
Jaubert-Miazza L, Green E, Lo FS, Bui K, Mills J, Guido W: Structural and functional composition of the developing retinogeniculate pathway in the mouse. Vis Neurosci 2005, 22:661–676.PubMedCrossRef
46.
Chu Y, Jin X, Parada I, Pesic A, Stevens B, Barres B, Prince DA: Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci USA 2010, 107:7975–7980.PubMedPubMedCentralCrossRef
47.
Crane JW, Baiquni GP, Sullivan RK, Lee JD, Sah P, Taylor SM, Noakes PG, Woodruff TM: The C5a anaphylatoxin receptor CD88 is expressed in presynaptic terminals of hippocampal mossy fibres. J Neuroinflammation 2009, 6:34.PubMedPubMedCentralCrossRef
48.
Pisalyaput K, Tenner AJ: Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem 2008, 104:696–707.PubMed
49.
Benoit ME, Tenner AJ: Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. J Neurosci 2011, 31:3459–3469.PubMedPubMedCentralCrossRef
50.
51.
Soane L, Rus H, Niculescu F, Shin ML: Inhibition of oligodendrocyte apoptosis by sublytic C5b-9 is associated with enhanced synthesis of bcl-2 and mediated by inhibition of caspase-3 activation. J Immunol 1999, 163:6132–6138.PubMed
52.
Cudrici C, Niculescu F, Jensen T, Zafranskaia E, Fosbrink M, Rus V, Shin ML, Rus H: C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP. J Immunol 2006, 176:3173–3180.PubMedCrossRef
53.
van Beek J, Nicole O, Ali C, Ischenko A, MacKenzie ET, Buisson A, Fontaine M: Complement anaphylatoxin C3a is selectively protective against NMDA-induced neuronal cell death. Neuroreport 2001, 12:289–293.PubMedCrossRef
54.
Heese K, Hock C, Otten U: Inflammatory signals induce neurotrophin expression in human microglial cells. J Neurochem 1998, 70:699–707.PubMedCrossRef
55.
Jauneau AC, Ischenko A, Chatagner A, Benard M, Chan P, Schouft MT, Patte C, Vaudry H, Fontaine M: Interleukin-1beta and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes. J Neuroinflammation 2006, 3:8.PubMedPubMedCentralCrossRef
56.
Osaka H, Mukherjee P, Aisen PS, Pasinetti GM: Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity. J Cell Biochem 1999, 73:303–311.PubMedCrossRef
57.
Mukherjee P, Pasinetti GM: Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. J Neurochem 2001, 77:43–49.PubMedCrossRef
58.
Mukherjee P, Thomas S, Pasinetti GM: Complement anaphylatoxin C5a neuroprotects through regulation of glutamate receptor subunit 2 in vitro and in vivo. J Neuroinflammation 2008, 5:5.PubMedPubMedCentralCrossRef
59.
Persson M, Pekna M, Hansson E, Ronnback L: The complement-derived anaphylatoxin C5a increases microglial GLT-1 expression and glutamate uptake in a TNF-alpha-independent manner. Eur J Neurosci 2009, 29:267–274.PubMedCrossRef
60.
Rahpeymai Y, Hietala MA, Wilhelmsson U, Fotheringham A, Davies I, Nilsson AK, Zwirner J, Wetsel RA, Gerard C, Pekny M, Pekna M: Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J 2006, 25:1364–1374.PubMedPubMedCentralCrossRef
61.
Benard M, Gonzalez BJ, Schouft MT, Falluel-Morel A, Vaudry D, Chan P, Vaudry H, Fontaine M: Characterization of C3a and C5a receptors in rat cerebellar granule neurons during maturation. Neuroprotective effect of C5a against apoptotic cell death. J Biol Chem 2004, 279:43487–43496.PubMedCrossRef
62.
Jurianz K, Ziegler S, Donin N, Reiter Y, Fishelson Z, Kirschfink M: K562 erythroleukemic cells are equipped with multiple mechanisms of resistance to lysis by complement. Int J Cancer 2001, 93:848–854.PubMedCrossRef
63.
Benard M, Raoult E, Vaudry D, Leprince J, Falluel-Morel A, Gonzalez BJ, Galas L, Vaudry H, Fontaine M: Role of complement anaphylatoxin receptors (C3aR, C5aR) in the development of the rat cerebellum. Mol Immunol 2008, 45:3767–3774.PubMedCrossRef
64.
Woodruff TM, Nandakumar KS, Tedesco F: Inhibiting the C5-C5a receptor axis. Mol Immunol 2011, 48:1631–1642.PubMedCrossRef
65.
Wagner E, Frank MM: Therapeutic potential of complement modulation. Nat Rev Drug Discov 2010, 9:43–56.PubMedCrossRef
66.
Morariu MA, Dalmasso AP: Experimental allergic encephalomyelitis in cobra venom factor-treated and C4-deficient guinea pigs. Ann Neurol 1978, 4:427–430.PubMedCrossRef
67.
Morgan BP, Campbell AK, Compston DA: Terminal component of complement (C9) in cerebrospinal fluid of patients with multiple sclerosis. Lancet 1984, 2:251–254.PubMedCrossRef
68.
Nataf S, Carroll SL, Wetsel RA, Szalai AJ, Barnum SR: Attenuation of experimental autoimmune demyelination in complement-deficient mice. J Immunol 2000, 165:5867–5873.PubMedCrossRef
69.
Niculescu T, Weerth S, Niculescu F, Cudrici C, Rus V, Raine CS, Shin ML, Rus H: Effects of complement C5 on apoptosis in experimental autoimmune encephalomyelitis. J Immunol 2004, 172:5702–5706.PubMedCrossRef
70.
Liu J, Miwa T, Hilliard B, Chen Y, Lambris JD, Wells AD, Song WC: The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med 2005, 201:567–577.PubMedPubMedCentralCrossRef
71.
Rus H, Cudrici C, Niculescu F, Shin ML: Complement activation in autoimmune demyelination: dual role in neuroinflammation and neuroprotection. J Neuroimmunol 2006, 180:9–16.PubMedCrossRef
72.
Li Q, Nacion K, Bu H, Lin F: The complement inhibitor FUT-175 suppresses T cell autoreactivity in experimental autoimmune encephalomyelitis. Am J Pathol 2009, 175:661–667.PubMedPubMedCentralCrossRef
73.
Ramaglia V, Hughes TR, Donev RM, Ruseva MM, Wu X, Huitinga I, Baas F, Neal JW, Morgan BP: C3-dependent mechanism of microglial priming relevant to multiple sclerosis. Proc Natl Acad Sci USA 2012, 109:965–970.PubMedPubMedCentralCrossRef
74.
Ingram G, Hakobyan S, Robertson NP, Morgan BP: Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol 2009, 155:128–139.PubMedPubMedCentralCrossRef
75.
Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ: Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J Neurochem 2008, 106:2080–2092.PubMedPubMedCentralCrossRef
76.
Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA: Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 2008, 28:6333–6341.PubMedPubMedCentralCrossRef
77.
Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD, LaFerla FM, Taylor SM, Woodruff TM, Tenner AJ: Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol 2009, 183:1375–1383.PubMedPubMedCentralCrossRef
78.
Veerhuis R: Histological and direct evidence for the role of complement in the neuroinflammation of AD. Curr Alzheimer Res 2011, 8:34–58.PubMedCrossRef
79.
Woodruff T, Crane J, Proctor L, Buller K, Shek A, de Vos K, Pollitt S, Williams H, Shiels I, Monk P, Taylor S: Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB J 2006, 20:1407–1417.PubMedCrossRef
80.
81.
Wang XJ, Yan ZQ, Lu GQ, Stuart S, Chen SD: Parkinson disease IgG and C5a-induced synergistic dopaminergic neurotoxicity: role of microglia. Neurochem Int 2007, 50:39–50.PubMedCrossRef
82.
Depboylu C, Schafer MK, Arias-Carrion O, Oertel WH, Weihe E, Hoglinger GU: Possible involvement of complement factor C1q in the clearance of extracellular neuromelanin from the substantia nigra in Parkinson disease. J Neuropathol Exp Neurol 2011, 70:125–132.PubMedCrossRef
83.
Rus H, Niculescu F: The complement system in central nervous system diseases. Immunol Res 2001, 24:79–86.PubMedCrossRef
84.
Woodruff TM, Costantini KJ, Crane JW, Atkin JD, Monk PN, Taylor SM, Noakes PG: The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol 2008, 181:8727–8734.PubMedCrossRef
85.
Woodruff TM, Costantini KJ, Taylor SM, Noakes PG: Role of complement in motor neuron disease: animal models and therapeutic potential of complement inhibitors. Adv Exp Med Biol 2008, 632:143–158.PubMed
86.
Heurich B, El Idrissi NB, Donev RM, Petri S, Claus P, Neal J, Morgan BP, Ramaglia V: Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. J Neuroimmunol 2011, 235:104–109.PubMedCrossRef
87.
Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP: Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 2000, 49:171–186.PubMedCrossRef
88.
Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P: Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol 2000, 157:905–918.PubMedPubMedCentralCrossRef
89.
Agoropoulou C, Piddlesden SJ, Lachmann PJ, Wing MG: Neuronal protection of oligodendrocytes from antibody-independent complement lysis. Neuroreport 1998, 9:927–932.PubMedCrossRef
90.
Alexander JJ, Anderson AJ, Barnum SR, Stevens B, Tenner AJ: The complement cascade: Yin-Yang in neuroinflammation–neuro-protection and -degeneration. J Neurochem 2008, 107:1169–1187.PubMedPubMedCentralCrossRef
91.
Galvan MD, Luchetti S, Burgos AM, Nguyen HX, Hooshmand MJ, Hamers FPT, Anderson AJ: Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury. J Neurosci 2008, 28:13876–13888.PubMedPubMedCentralCrossRef
92.
Arumugam TV, Woodruff TM, Lathia JD, Selvaraj PK, Mattson MP, Taylor SM: Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience 2009, 158:1074–1089.PubMedCrossRef
93.
Qiao F, Atkinson C, Song H, Pannu R, Singh I, Tomlinson S: Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma. Am J Pathol 2006, 169:1039–1047.PubMedPubMedCentralCrossRef
94.
Guo Q, Li S, Liang Y, Zhang Y, Zhang J, Wen C, Lin S, Wang H, Su B: Effects of C3 deficiency on inflammation and regeneration following spinal cord injury in mice. Neurosci Lett 2010, 485:32–36.PubMedCrossRef
95.
Kato H, Kogure K: Biochemical and molecular characteristics of the brain with developing cerebral infarction. Cell Mol Neurobiol 1999, 19:93–108.PubMedCrossRef
96.
Mocco J, Wilson DA, Komotar RJ, Sughrue ME, Coates K, Sacco RL, Elkind MS, Connolly ES: Alterations in plasma complement levels after human ischemic stroke. Neurosurgery 2006, 59:28–33. discussion 28–33PubMedCrossRef
97.
Pedersen ED, Loberg EM, Vege E, Daha MR, Maehlen J, Mollnes TE: In situ deposition of complement in human acute brain ischaemia. Scand J Immunol 2009, 69:555–562.PubMedCrossRef
98.
Cervera A, Planas AM, Justicia C, Urra X, Jensenius JC, Torres F, Lozano F, Chamorro A: Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One 2010, 5:e8433.PubMedPubMedCentralCrossRef
99.
Morrison H, Frye J, Davis-Gorman G, Funk J, McDonagh P, Stahl G, Ritter L: The contribution of mannose binding lectin to reperfusion injury after ischemic stroke. Curr Neurovasc Res 2011, 8:52–63.PubMedPubMedCentralCrossRef
100.
Gesuete R, Storini C, Fantin A, Stravalaci M, Zanier ER, Orsini F, Vietsch H, Mannesse ML, Ziere B, Gobbi M, De Simoni MG: Recombinant C1 inhibitor in brain ischemic injury. Ann Neurol 2009, 66:332–342.PubMedCrossRef
101.
Schafer MK, Schwaeble WJ, Post C, Salvati P, Calabresi M, Sim RB, Petry F, Loos M, Weihe E: Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. J Immunol 2000, 164:5446–5452.PubMedCrossRef
102.
Mack WJ, Sughrue ME, Ducruet AF, Mocco J, Sosunov SA, Hassid BG, Silverberg JZ, Ten VS, Pinsky DJ, Connolly ES: Temporal pattern of C1q deposition after transient focal cerebral ischemia. J Neurosci Res 2006, 83:883–889.PubMedCrossRef
103.
Ten VS, Sosunov SA, Mazer SP, Stark RI, Caspersen C, Sughrue ME, Botto M, Connolly ES, Pinsky DJ: C1q-deficiency is neuroprotective against hypoxic-ischemic brain injury in neonatal mice. Stroke 2005, 36:2244–2250.PubMedCrossRef
104.
Mocco J, Mack WJ, Ducruet AF, Sosunov SA, Sughrue ME, Hassid BG, Nair MN, Laufer I, Komotar RJ, Claire M, Holland H, Pinsky DJ, Connolly ES: Complement component c3 mediates inflammatory injury following focal cerebral ischemia. Circ Res 2006, 99:209–217.PubMedCrossRef
105.
Reichwald J, Danner S, Wiederhold KH, Staufenbiel M: Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation 2009, 6:35.PubMedPubMedCentralCrossRef
106.
De Simoni MG, Rossi E, Storini C, Pizzimenti S, Echart C, Bergamaschini L: The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol 2004, 164:1857–1863.PubMedPubMedCentralCrossRef
107.
Akita N, Nakase H, Kaido T, Kanemoto Y, Sakaki T: Protective effect of C1 esterase inhibitor on reperfusion injury in the rat middle cerebral artery occlusion model. Neurosurgery 2003, 52:395–400. discussion 400–1PubMedCrossRef
108.
Kishimoto T, Akira S, Narazaki M, Taga T: Interleukin-6 family of cytokines and gp130. Blood 1995, 86:1243–1254.PubMed
109.
Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK: IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998, 101:311–320.PubMedPubMedCentralCrossRef
110.
Storini C, Rossi E, Marrella V, Distaso M, Veerhuis R, Vergani C, Bergamaschini L, De Simoni MG: C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation. Neurobiol Dis 2005, 19:10–17.PubMedCrossRef
111.
Huang J, Kim LJ, Mealey R, Marsh HC, Zhang Y, Tenner AJ, Connolly ES, Pinsky DJ: Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 1999, 285:595–599.PubMedCrossRef
112.
Huang Y, Qiao F, Atkinson C, Holers VM, Tomlinson S: A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury. J Immunol 2008, 181:8068–8076.PubMedPubMedCentralCrossRef
113.
Mocco J, Mack WJ, Ducruet AF, King RG, Sughrue ME, Coon AL, Sosunov SA, Sciacca RR, Zhang Y, Marsh HC, Pinsky DJ, Connolly ES: Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke. J Neurosurg 2006, 105:595–601.PubMedCrossRef
114.
Atkinson C, He S, Morris K, Qiao F, Casey S, Goddard M, Tomlinson S: Targeted complement inhibitors protect against posttransplant cardiac ischemia and reperfusion injury and reveal an important role for the alternative pathway of complement activation. J Immunol 2010, 185:7007–7013.PubMedCrossRef
115.
Arumugam TV, Tang SC, Lathia JD, Cheng A, Mughal MR, Chigurupati S, Magnus T, Chan SL, Jo DG, Ouyang X, Fairlie DP, Granger DN, Vortmeyer A, Basta M, Mattson MP: Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proc Natl Acad Sci USA 2007, 104:14104–14109.PubMedPubMedCentralCrossRef
116.
Costa C, Zhao L, Shen Y, Su X, Hao L, Colgan SP, Stahl GL, Zhou T, Wang Y: Role of complement component C5 in cerebral ischemia/reperfusion injury. Brain Res 2006, 1100:142–151.PubMedCrossRef
117.
Pavlovski D, Thundyil J, Monk PN, Wetsel RA, Taylor SM, Woodruff TM: Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB J 2012,:. in press
118.
Ten VS, Yao J, Ratner V, Sosunov S, Fraser DA, Botto M, Sivasankar B, Morgan BP, Silverstein S, Stark R, Polin R, Vannucci SJ, Pinsky D, Starkov AA: Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury. J Neurosci 2010, 30:2077–2087.PubMedPubMedCentralCrossRef
119.
Harhausen D, Khojasteh U, Stahel PF, Morgan BP, Nietfeld W, Dirnagl U, Trendelenburg G: Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice. J Neuroinflammation 2010, 7:15.PubMedPubMedCentralCrossRef
120.
Nishino H, Czurko A, Fukuda A, Hashitani T, Hida H, Karadi Z, Lenard L: Pathophysiological process after transient ischemia of the middle cerebral artery in the rat. Brain Res Bull 1994, 35:51–56.PubMedCrossRef
121.
Barnum SR, Ames RS, Maycox PR, Hadingham SJ, Meakin J, Harrison D, Parsons AA: Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation. Glia 2002, 38:169–173.PubMedCrossRef
122.
Ducruet AF, Hassid BG, Mack WJ, Sosunov SA, Otten ML, Fusco DJ, Hickman ZL, Kim GH, Komotar RJ, Mocco J, Connolly ES: C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent. J Cereb Blood Flow Metab 2008, 28:1048–1058.PubMedCrossRef
123.
Proctor LM, Arumugam TV, Shiels I, Reid RC, Fairlie DP, Taylor SM: Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury. Br J Pharmacol 2004, 142:756–764.PubMedPubMedCentralCrossRef
124.
Mathieu MC, Sawyer N, Greig GM, Hamel M, Kargman S, Ducharme Y, Lau CK, Friesen RW, O'Neill GP, Gervais FG, Therien AG: The C3a receptor antagonist SB 290157 has agonist activity. Immunol Lett 2005, 100:139–145.PubMedCrossRef
125.
Therien AG: Agonist activity of the small molecule C3aR ligand SB 290157. J Immunol 2005, 174:7479–7480.PubMedCrossRef
126.
Kim GH, Mocco J, Hahn DK, Kellner CP, Komotar RJ, Ducruet AF, Mack WJ, Connolly ES: Protective effect of C5a receptor inhibition after murine reperfused stroke. Neurosurgery 2008, 63:122–125. discussion 125–6PubMedPubMedCentralCrossRef
127.
Bellander B-M, Singhrao SK, Ohlsson M, Mattsson P, Svensson M: Complement activation in the human brain after traumatic head injury. J Neurotrauma 2001, 18:1295–1311.PubMedCrossRef
128.
Stahel PF, Morganti-Kossmann MC, Kossmann T: The role of the complement system in traumatic brain injury. Brain Res Brain Res Rev 1998, 27:243–256.PubMedCrossRef
129.
Kossmann T, Stahel PF, Morganti-Kossmann MC, Jones JL, Barnum SR: Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J Neuroimmunol 1997, 73:63–69.PubMedCrossRef
130.
Stahel PF, Morganti-Kossmann MC, Perez D, Redaelli C, Gloor B, Trentz O, Kossmann T: 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 2001, 18:773–781.PubMedCrossRef
131.
Bellander BM, von Holst H, Fredman P, Svensson M: Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat. J Neurosurg 1996, 85:468–475.PubMedCrossRef
132.
Leinhase I, Holers VM, Thurman JM, Harhausen D, Schmidt OI, Pietzcker M, Taha ME, Rittirsch D, Huber-Lang M, Smith WR, Ward PA, Stahel PF: Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation. BMC Neurosci 2006, 7:55.PubMedPubMedCentralCrossRef
133.
Leinhase I, Rozanski M, Harhausen D, Thurman JM, Schmidt OI, Hossini AM, Taha ME, Rittirsch D, Ward PA, Holers VM, Ertel W, Stahel PF: Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice. J Neuroinflammation 2007, 4:13.PubMedPubMedCentralCrossRef
134.
Longhi L, Perego C, Ortolano F, Zanier ER, Bianchi P, Stocchetti N, McIntosh TK, De Simoni MG: C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice. Crit Care Med 2009, 37:659–665.PubMedCrossRef
135.
Yang S, Nakamura T, Hua Y, Keep RF, Younger JG, He Y, Hoff JT, Xi G: The role of complement C3 in intracerebral hemorrhage-induced brain injury. J Cereb Blood Flow Metab 2006, 26:1490–1495.PubMedCrossRef
136.
Sewell DL, Nacewicz B, Liu F, Macvilay S, Erdei A, Lambris JD, Sandor M, Fabry Z: Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist. J Neuroimmunol 2004, 155:55–63.PubMedPubMedCentralCrossRef
137.
Rancan M, Morganti-Kossmann MC, Barnum SR, Saft S, Schmidt OI, Ertel W, Stahel PF: Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice. J Cereb Blood Flow Metab 2003, 23:1070–1074.PubMedCrossRef
138.
Leinhase I, Schmidt OI, Thurman JM, Hossini AM, Rozanski M, Taha ME, Scheffler A, John T, Smith WR, Holers VM, Stahel PF: Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury. Exp Neurol 2006, 199:454–464.PubMedCrossRef
139.
Stahel PF, Flierl MA, Morgan BP, Persigehl I, Stoll C, Conrad C, Touban BM, Smith WR, Beauchamp K, Schmidt OI, Ertel W, Leinhase I: Absence of the complement regulatory molecule CD59a leads to exacerbated neuropathology after traumatic brain injury in mice. J Neuroinflammation 2009, 6:2.PubMedPubMedCentralCrossRef
140.
Garrett MC, Otten ML, Starke RM, Komotar RJ, Magotti P, Lambris JD, Rynkowski MA, Connolly ES: Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res 2009, 1298:171–177.PubMedCrossRef
141.
Hausmann ON: Post-traumatic inflammation following spinal cord injury. Spinal Cord 2003, 41:369–378.PubMedCrossRef
142.
Dumont RJO, David O, Subodh Verma , Hurlbert , John R, Boulos , Paul T, Ellegala , Dilantha B, Dumont , Aaron S: Acute spinal cord injury, part i: pathophysiologic mechanisms. Clin Neuropharmacol 2001, 24:254–264.PubMedCrossRef
143.
Reynolds DN, Smith SA, Zhang YP, Mengsheng Q, Lahiri DK, Morassutti DJ, Shields CB, Kotwal GJ: Vaccinia virus complement control protein reduces inflammation and improves spinal cord integrity following spinal cord injury. Ann N Y Acad Sci 2004, 1035:165–178.PubMedCrossRef
144.
Li LM, Li JB, Zhu Y, Fan GY: Soluble complement receptor type 1 inhibits complement system activation and improves motor function in acute spinal cord injury. Spinal Cord 2009, 48:105–111.PubMedCrossRef
145.
Banda NK, Hyatt S, Antonioli AH, White JT, Glogowska M, Takahashi K, Merkel TJ, Stahl GL, Mueller-Ortiz S, Wetsel R, Arend WP, Holers VM: Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice. J Immunol 2012, 188:1469–1478.PubMedCrossRef
146.
Rossignol S, Frigon A: Recovery of locomotion after spinal cord injury: some facts and mechanisms. Annu Rev Neurosci 2011, 34:413–440.PubMedCrossRef
147.
Rice CE: The interchangeability of the complement components of different animal species; literature survey. Can J Comp Med Vet Sci 1950, 14:369–379.PubMedPubMedCentral
148.
Drake WP, Ungaro PC, Mardiney MR: The measurement and manipulation of hemolytic complement levels in tumor bearing C57BL/6 mice. Biomedicine 1973, 18:284–289.PubMed
149.
Grant CK: Complement origin determines lytic activity of antibodies to nucleated target cells. Comparison of common complement sources. Transplantation 1976, 21:323–330.PubMedCrossRef
150.
Ebanks RO, Isenman DE: Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity. Mol Immunol 1996, 33:297–309.PubMedCrossRef
151.
Ong GL, Mattes MJ: Mouse strains with typical mammalian levels of complement activity. J Immunol Methods 1989, 125:147–158.PubMedCrossRef
Metadata
Title
Complement activation in the injured central nervous system: another dual-edged sword?
Authors
Faith H Brennan
Aileen J Anderson
Stephen M Taylor
Trent M Woodruff
Marc J Ruitenberg
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-137

Other articles of this Issue 1/2012

Journal of Neuroinflammation 1/2012 Go to the issue

Research

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Research

Podosomes in migrating microglia: components and matrix degradation

Short report

Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability

Research

The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor

Research

Immunoadsorption therapy in patients with multiple sclerosis with steroid-refractory optical neuritis

Research

c-Src-dependent EGF receptor transactivation contributes to ET-1-induced COX-2 expression in brain microvascular endothelial cells