title: The complement cascade: Yin-Yang in neuroinflammation--neuro-protection and -degeneration.
abstract: The complement cascade has long been recognized to play a key role in inflammatory and degenerative diseases. It is a 'double edged' sword as it is necessary to maintain health, yet can have adverse effects when unregulated, often exacerbating disease. The contrasting effects of complement, depending on whether in a setting of health or disease, is the price paid to achieve flexibility in scope and degree of a protective response for the host from infection and injury. Loss or even decreased efficiency of critical regulatory control mechanisms can result in aggravated inflammation and destruction of self-tissue. The role of the complement cascade is poorly understood in the nervous system and neurological disorders. Novel studies have demonstrated that the expression of complement proteins in brain varies in different cell types and the effects of complement activation in various disease settings appear to differ. Understanding the functioning of this cascade is essential, as it has therapeutic implications. In this review, we will attempt to provide insight into how this complex cascade functions and to identify potential strategic targets for therapeutic intervention in chronic diseases as well as acute injury in the CNS.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA. jalexand@medicine.bsd.uchicago.edu
authors.forename: Jessy John
authors.initials: JJ
authors.lastname: Alexander
authors.forename: Aileen Judith
authors.initials: AJ
authors.lastname: Anderson
authors.forename: Scott Robert
authors.initials: SR
authors.lastname: Barnum
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.forename: Andrea Joan
authors.initials: AJ
authors.lastname: Tenner
mesh_terms: D003167:Complement Activation / Q000502:physiology; D003165:Complement System Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D009422:Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D016709:Yin-Yang
chemical_list: D003165:Complement System Proteins
references.citation: Annu Rev Med. 2007;58:417-32
references.pmid: 17217332
references.citation: J Neuroinflammation. 2008 Mar 11;5:9
references.pmid: 18334032
references.citation: Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1247-58
references.pmid: 15037594
references.citation: J Immunol. 2000 Nov 15;165(10):5867-73
references.pmid: 11067947
references.citation: Lupus. 1997;6(8):645-51
references.pmid: 9364423
references.citation: Eur J Immunol. 2007 Jun;37(6):1691-701
references.pmid: 17523212
references.citation: J Neuroimmunol. 2006 Nov;180(1-2):3-8
references.pmid: 16934338
references.citation: Arthritis Rheum. 1990 Oct;33(10):1598-9
references.pmid: 2222545
references.citation: Alzheimer Dis Assoc Disord. 2005 Apr-Jun;19(2):55-66
references.pmid: 15942322
references.citation: Brain Res Mol Brain Res. 1992 Jun;14(1-2):109-16
references.pmid: 1323007
references.citation: Curr Pharm Des. 2005;11(10):1223-36
references.pmid: 15853679
references.citation: Clin Dermatol. 1984 Jul-Sep;2(3):17-23
references.pmid: 6545766
references.citation: Ann N Y Acad Sci. 2004 Dec;1035:165-78
references.pmid: 15681807
references.citation: Biochim Biophys Acta. 2003 Nov 20;1639(3):169-76
references.pmid: 14636948
references.citation: J Comp Neurol. 1991 Dec 1;314(1):125-35
references.pmid: 1797868
references.citation: Arthritis Rheum. 1988 May;31(5):632-41
references.pmid: 3259882
references.citation: J Neurosci Res. 1990 Sep;27(1):36-42
references.pmid: 2254955
references.citation: Neurobiol Aging. 1996 Sep-Oct;17(5):695-705
references.pmid: 8892342
references.citation: Neuroscience. 2000;96(4):807-15
references.pmid: 10727798
references.citation: J Immunol. 1999 Dec 1;163(11):6132-8
references.pmid: 10570303
references.citation: Arthritis Rheum. 1996 Jan;39(1):9-22
references.pmid: 8546744
references.citation: Ann Rheum Dis. 2005 Aug;64(8):1210-3
references.pmid: 15708887
references.citation: Blood. 2007 Jul 1;110(1):228-36
references.pmid: 17363730
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: Biochem J. 1983 Nov 15;216(2):385-92
references.pmid: 6318736
references.citation: Neurosci Lett. 2001 Jun 15;305(3):165-8
references.pmid: 11403931
references.citation: Clin Immunol. 2005 Jun;115(3):225-35
references.pmid: 15893689
references.citation: Ann Neurol. 1998 Apr;43(4):465-71
references.pmid: 9546327
references.citation: Res Immunol. 1992 Jul-Aug;143(6):624-30
references.pmid: 1455054
references.citation: J Exp Med. 1988 Oct 1;168(4):1225-35
references.pmid: 3262708
references.citation: Glia. 2005 Jan 1;49(1):158-60
references.pmid: 15390104
references.citation: Brain Res Bull. 1999 Aug;49(6):377-91
references.pmid: 10483914
references.citation: Neurosurg Clin N Am. 2007 Jan;18(1):143-68, xi
references.pmid: 17244561
references.citation: J Immunol. 2005 Nov 15;175(10):6327-33
references.pmid: 16272284
references.citation: J Exp Med. 2003 Sep 15;198(6):913-23
references.pmid: 12975457
references.citation: J Neuroinflammation. 2005 Dec 07;2:28
references.pmid: 16332263
references.citation: Invest Ophthalmol Vis Sci. 2006 Mar;47(3):1024-9
references.pmid: 16505037
references.citation: J Neurosci. 1999 Oct 1;19(19):8182-98
references.pmid: 10493720
references.citation: Arthritis Rheum. 1997 Jan;40(1):36-46
references.pmid: 9008598
references.citation: J Biol Chem. 1999 Jun 4;274(23):16349-54
references.pmid: 10347193
references.citation: Neurology. 2002 Apr 23;58(8):1214-20
references.pmid: 11971089
references.citation: Nature. 2008 Feb 7;451(7179):720-4
references.pmid: 18256671
references.citation: Brain Res Rev. 2006 Aug 30;52(1):58-68
references.pmid: 16443278
references.citation: J Immunol Methods. 1989 Dec 20;125(1-2):147-58
references.pmid: 2607149
references.citation: Nat Genet. 1998 May;19(1):56-9
references.pmid: 9590289
references.citation: Curr Neurol Neurosci Rep. 2003 May;3(3):246-55
references.pmid: 12691630
references.citation: J Rheumatol. 1999 Feb;26(2):432-9
references.pmid: 9972981
references.citation: Folia Neuropathol. 1998;36(3):145-51
references.pmid: 9833391
references.citation: Lupus. 2006;15(5):308-18
references.pmid: 16761508
references.citation: J Neurotrauma. 2006 Mar-Apr;23(3-4):371-83
references.pmid: 16629623
references.citation: J Immunol. 1990 Mar 1;144(5):1549-53
references.pmid: 2307833
references.citation: J Cell Biochem. 1999 Jun 1;73(3):303-11
references.pmid: 10321830
references.citation: Ann Neurol. 1978 Nov;4(5):427-30
references.pmid: 83812
references.citation: Neurobiol Aging. 1996 Nov-Dec;17(6):921-33
references.pmid: 9363804
references.citation: Acta Neurol Scand. 2000 Feb;101(2):116-21
references.pmid: 10685859
references.citation: Nat Med. 1997 Jan;3(1):73-6
references.pmid: 8986744
references.citation: Am J Pathol. 2001 Apr;158(4):1345-54
references.pmid: 11290552
references.citation: Ann Neurol. 2004 Apr;55(4):458-68
references.pmid: 15048884
references.citation: Lupus. 2003;12(12):908-15
references.pmid: 14714910
references.citation: Brain Behav Immun. 1992 Sep;6(3):265-85
references.pmid: 1392101
references.citation: Eur J Immunol. 2002 Apr;32(4):1157-63
references.pmid: 11932923
references.citation: Trends Immunol. 2006 Apr;27(4):167-8
references.pmid: 16513422
references.citation: J Neuropathol Exp Neurol. 1996 Oct;55(10):1083-8
references.pmid: 8858005
references.citation: Lupus. 2003;12(1):3-7
references.pmid: 12587819
references.citation: Lancet. 1984 Aug 4;2(8397):251-4
references.pmid: 6146808
references.citation: J Immunol. 2006 Nov 15;177(10):7266-74
references.pmid: 17082645
references.citation: J Neurochem. 2001 Apr;77(1):43-9
references.pmid: 11279260
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: Annu Rev Neurosci. 1999;22:389-442
references.pmid: 10202544
references.citation: Trends Immunol. 2004 Dec;25(12):632-6
references.pmid: 15530830
references.citation: J Neurosci. 2008 Jan 2;28(1):264-78
references.pmid: 18171944
references.citation: J Cell Biol. 2005 Oct 24;171(2):313-25
references.pmid: 16247030
references.citation: Vis Neurosci. 2005 Sep-Oct;22(5):637-48
references.pmid: 16332275
references.citation: Rheumatol Int. 2002 Jan;21(4):149-52
references.pmid: 11843170
references.citation: Lancet Neurol. 2005 Jul;4(7):403-12
references.pmid: 15963443
references.citation: J Exp Med. 2007 Jun 11;204(6):1319-25
references.pmid: 17548523
references.citation: Adv Exp Med Biol. 2006;586:139-51
references.pmid: 16893070
references.citation: J Immunol. 2006 Mar 1;176(5):3173-80
references.pmid: 16493077
references.citation: J Neurosci. 2004 Mar 3;24(9):2143-55
references.pmid: 14999065
references.citation: J Neurosci. 2008 Jun 18;28(25):6333-41
references.pmid: 18562603
references.citation: J Neurosci. 1998 Sep 1;18(17):6713-22
references.pmid: 9712643
references.citation: J Neurosci. 2008 Dec 17;28(51):13876-88
references.pmid: 19091977
references.citation: J Comp Neurol. 2006 Feb 1;494(4):578-94
references.pmid: 16374800
references.citation: Brain. 2006 Dec;129(Pt 12):3249-69
references.pmid: 17071951
references.citation: J Immunol. 2006 Oct 15;177(8):4953-6
references.pmid: 17015675
references.citation: Annu Rev Immunol. 2005;23:683-747
references.pmid: 15771584
references.citation: J Pain. 2005 Mar;6(3):174-83
references.pmid: 15772911
references.citation: J Immunol. 1999 Dec 15;163(12):6551-6
references.pmid: 10586048
references.citation: Nat Neurosci. 2004 Apr;7(4):327-32
references.pmid: 15048120
references.citation: Neuroscience. 1985 Jun;15(2):313-26
references.pmid: 3895031
references.citation: Neuroscientist. 2005 Oct;11(5):400-7
references.pmid: 16151042
references.citation: J Immunol. 2004 Oct 1;173(7):4708-14
references.pmid: 15383607
references.citation: Curr Opin Neurol. 2003 Jun;16(3):259-65
references.pmid: 12858060
references.citation: Cell. 2005 Feb 25;120(4):545-55
references.pmid: 15734686
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):146-56
references.pmid: 14735117
references.citation: J Exp Med. 1998 Aug 3;188(3):431-8
references.pmid: 9687521
references.citation: J Immunol. 2008 Jan 15;180(2):1231-8
references.pmid: 18178863
references.citation: Curr Opin Immunol. 1996 Dec;8(6):843-51
references.pmid: 8994865
references.citation: Curr Neurol Neurosci Rep. 2007 May;7(3):231-8
references.pmid: 17488589
references.citation: Learn Mem. 2001 Nov-Dec;8(6):301-8
references.pmid: 11773429
references.citation: Int Arch Allergy Immunol. 2004 Aug;134(4):310-23
references.pmid: 15218334
references.citation: Acta Neuropathol. 1990;80(4):415-8
references.pmid: 2239153
references.citation: Trends Pharmacol Sci. 2003 Jan;24(1):13-7
references.pmid: 12498725
references.citation: Nat Rev Neurosci. 2002 Mar;3(3):216-27
references.pmid: 11994753
references.citation: Mol Neurobiol. 2002 Oct-Dec;26(2-3):299-316
references.pmid: 12428762
references.citation: Hippocampus. 1998;8(5):458-74
references.pmid: 9825958
references.citation: Medicine (Baltimore). 1971 Mar;50(2):85-95
references.pmid: 4109481
references.citation: Curr Opin Neurol. 2007 Jun;20(3):343-50
references.pmid: 17495631
references.citation: Neuron. 2006 Oct 19;52(2):281-91
references.pmid: 17046691
references.citation: Cell. 2007 Dec 14;131(6):1164-78
references.pmid: 18083105
references.citation: Brain Behav Immun. 2008 Aug;22(6):838-49
references.pmid: 18255258
references.citation: Neuroscience. 1994 Oct;62(3):741-58
references.pmid: 7870303
references.citation: Immunopharmacology. 2000 Aug;49(1-2):171-86
references.pmid: 10904116
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8955-9
references.pmid: 7568051
references.citation: Brain Res. 1998 Nov 16;811(1-2):111-21
references.pmid: 9804916
references.citation: J Rheumatol. 1997 Dec;24(12):2323-9
references.pmid: 9415636
references.citation: Mol Immunol. 2006 Apr;43(10):1722-5
references.pmid: 16310250
references.citation: EMBO J. 2006 Mar 22;25(6):1364-74
references.pmid: 16498410
references.citation: Eur J Immunol. 2002 Mar;32(3):783-92
references.pmid: 11870622
references.citation: Am J Pathol. 2006 Sep;169(3):1039-47
references.pmid: 16936276
references.citation: Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4347-56
references.pmid: 14507879
references.citation: Ann Neurol. 2000 Jun;47(6):707-17
references.pmid: 10852536
references.citation: J Neuropathol Exp Neurol. 2005 Feb;64(2):147-55
references.pmid: 15751229
references.citation: Science. 1996 Nov 15;274(5290):1133-8
references.pmid: 8895456
references.citation: J Neurosci. 2007 Aug 8;27(32):8699-708
references.pmid: 17687047
references.citation: Ann Med. 2005;37(2):97-104
references.pmid: 16026117
references.citation: J Neurosci. 2004 Jul 21;24(29):6457-65
references.pmid: 15269255
references.citation: Nature. 1997 Dec 18-25;390(6661):680-3
references.pmid: 9414159
references.citation: J Immunol. 1995 May 1;154(9):4726-33
references.pmid: 7536777
references.citation: J Cell Physiol. 2000 Nov;185(2):280-92
references.pmid: 11025450
references.citation: BMC Genet. 2007 Jul 03;8:45
references.pmid: 17608931
references.citation: Autoimmunity. 2006 Aug;39(5):395-402
references.pmid: 16923539
references.citation: Neurochem Int. 2005 Jul;47(1-2):143-51
references.pmid: 15893408
references.citation: Invest Ophthalmol Vis Sci. 2006 Mar;47(3):977-85
references.pmid: 16505032
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2173-8
references.pmid: 14769913
references.citation: J Neurosci. 2007 Jul 18;27(29):7663-72
references.pmid: 17634361
references.citation: Ann Neurol. 2006 Jul;60(1):12-21
references.pmid: 16802293
references.citation: J Immunol. 2002 Jan 1;168(1):458-65
references.pmid: 11751993
references.citation: J Neurochem. 2007 Aug;102(3):900-12
references.pmid: 17561941
references.citation: J Neuropathol Exp Neurol. 2005 Aug;64(8):722-9
references.pmid: 16106221
references.citation: Science. 1996 Oct 4;274(5284):99-102
references.pmid: 8810256
references.citation: Expert Rev Clin Immunol. 2006 May;2(3):445-56
references.pmid: 20476915
references.citation: Cell Mol Life Sci. 2008 Jan;65(1):161-76
references.pmid: 17975707
references.citation: Nat Immunol. 2007 Sep;8(9):913-9
references.pmid: 17712344
references.citation: Magn Reson Imaging. 2003 Nov;21(9):1033-7
references.pmid: 14684208
references.citation: J Immunol. 1994 May 15;152(10):5050-9
references.pmid: 8176223
references.citation: J Rehabil Res Dev. 2006 Jan-Feb;43(1):123-32
references.pmid: 16847778
references.citation: Exp Neurol. 2008 Feb;209(2):378-88
references.pmid: 17662717
references.citation: Neurobiol Aging. 2004 Sep;25(8):1001-7
references.pmid: 15212824
references.citation: J Neuroinflammation. 2008 Jan 29;5:5
references.pmid: 18230183
references.citation: Am J Pathol. 2003 Sep;163(3):1069-80
references.pmid: 12937147
references.citation: Am J Pathol. 2000 Feb;156(2):489-99
references.pmid: 10666378
references.citation: J Leukoc Biol. 2006 Jul;80(1):107-16
references.pmid: 16617157
references.citation: Curr Opin Neurobiol. 2005 Oct;15(5):542-8
references.pmid: 16144764
references.citation: J Neurochem. 2008 Sep;106(5):2080-92
references.pmid: 18624920
references.citation: J Glaucoma. 1999 Dec;8(6):400-12
references.pmid: 10604301
references.citation: J Clin Invest. 2005 Sep;115(9):2444-53
references.pmid: 16127466
references.citation: Prog Neurobiol. 2003 Aug;70(6):463-72
references.pmid: 14568360
references.citation: J Immunol. 2005 Dec 15;175(12):8312-9
references.pmid: 16339572
references.citation: Ann Allergy. 1980 May;44(5):287-8
references.pmid: 6966477
references.citation: Neurology. 1990 May;40(5):855-7
references.pmid: 2330118
references.citation: Arthritis Rheum. 1986 Sep;29(9):1085-9
references.pmid: 3489467
references.citation: J Neurotrauma. 2005 Mar;22(3):382-97
references.pmid: 15785233
references.citation: J Neurochem. 2008 Feb;104(3):696-707
references.pmid: 17986223
references.citation: J Immunol Methods. 1992 Sep 18;154(1):37-45
references.pmid: 1401942
references.citation: Arthritis Rheum. 1992 Jan;35(1):55-61
references.pmid: 1731815
references.citation: J Neurosci. 2004 Apr 28;24(17):4181-6
references.pmid: 15115813
references.citation: J Neurotrauma. 2004 Dec;21(12):1831-46
references.pmid: 15684772
references.citation: Neurosci Lett. 2005 Dec 30;390(3):134-8
references.pmid: 16154690
references.citation: Neurochem Int. 2007 Jan;50(1):5-11
references.pmid: 16989923
references.citation: Arch Ophthalmol. 1997 Jun;115(6):752-6
references.pmid: 9194727
references.citation: Mol Cell Neurosci. 2002 May;20(1):125-39
references.pmid: 12056844
references.citation: J Spinal Cord Med. 2002 Summer;25(2):70-9; discussion 80
references.pmid: 12137220
references.citation: Exp Neurol. 1996 Mar;138(1):22-32
references.pmid: 8593893
references.citation: J Peripher Nerv Syst. 1999;4(2):123-33
references.pmid: 10442688
references.citation: Mol Immunol. 2007 Jan;44(1-3):33-43
references.pmid: 16908067
references.citation: Mol Immunol. 2008 Mar;45(5):1199-207
references.pmid: 17961651
references.citation: Brain Pathol. 1994 Jul;4(3):229-37
references.pmid: 7952264
references.citation: Neurobiol Aging. 1997 Jul-Aug;18(4):415-21
references.pmid: 9330973
references.citation: Glia. 2004 Aug 15;47(3):209-16
references.pmid: 15252809
references.citation: Nat Biotechnol. 2007 Nov;25(11):1265-75
references.pmid: 17989689
references.citation: J Immunol. 1998 Nov 1;161(9):4480-3
references.pmid: 9794370
references.citation: Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;47(1):17-25
references.pmid: 6151285
references.citation: J Cereb Blood Flow Metab. 2007 Jun;27(6):1096-107
references.pmid: 17033690
references.citation: J Neuroinflammation. 2008 Jun 25;5:26
references.pmid: 18578885
references.citation: Nat Med. 2006 Jun;12(6):682-7
references.pmid: 16715088
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10837-42
references.pmid: 12119423
references.citation: Am J Pathol. 2007 Jun;170(6):2001-8
references.pmid: 17525267
references.citation: Lupus. 2002;11(2):102-8
references.pmid: 11958572