title: The membrane attack complex of the complement system is essential for rapid Wallerian degeneration.
abstract: The complement (C) system plays an important role in myelin breakdown during Wallerian degeneration (WD). The pathway and mechanism involved are, however, not clear. In a crush injury model of the sciatic nerve, we show that C6, necessary for the assembly of the membrane attack complex (MAC), is essential for rapid WD. At 3 d after injury, pronounced WD occurred in wild-type animals, whereas the axons and myelin of C6-deficient animals appeared intact. Macrophage recruitment and activation was inhibited in C6-deficient rats. However, 7 d after injury, the distal part of the C6-deficient nerves appeared degraded. As a consequence of a delayed WD, more myelin breakdown products were present than in wild-type nerves. Reconstitution of the C6-deficient animals with C6 restored the wild-type phenotype. Treatment with rhC1INH (recombinant human complement 1 inhibitor) blocked deposition of activated C-cleaved products after injury. These experiments demonstrate that the classical pathway of the complement system is activated after acute nerve trauma and that the entire complement cascade, including MAC deposition, is essential for rapid WD and efficient clearance of myelin after acute peripheral nerve trauma.
authors.affiliation: Neurogenetics Laboratory, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ramaglia
authors.forename: Rosalind Helen Mary
authors.initials: RH
authors.lastname: King
authors.forename: Michelle
authors.initials: M
authors.lastname: Nourallah
authors.forename: Ruud
authors.initials: R
authors.lastname: Wolterman
authors.forename: Rosalein
authors.initials: R
authors.lastname: de Jonge
authors.forename: Marja
authors.initials: M
authors.lastname: Ramkema
authors.forename: Miriam Ann
authors.initials: MA
authors.lastname: Vigar
authors.forename: Sandra
authors.initials: S
authors.lastname: van der Wetering
authors.forename: Brian Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D003174:Complement C1 Inactivator Proteins / Q000008:administration & dosage; D050718:Complement C1 Inhibitor Protein; D003183:Complement C6 / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism*; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017730:Ki-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020426:Sciatic Neuropathy / Q000150:complications / Q000473:pathology; D015843:Serpins / Q000008:administration & dosage; D014855:Wallerian Degeneration / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D017730:Ki-1 Antigen; D016900:Neurofilament Proteins; D015843:Serpins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C469952:SERPING1 protein, human