The membrane attack complex of the complement system is essential for rapid Wallerian degeneration.
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.
Ramaglia
Valeria
V
Neurogenetics Laboratory, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
King
Rosalind Helen Mary
RH
Nourallah
Michelle
M
Wolterman
Ruud
R
de Jonge
Rosalein
R
Ramkema
Marja
M
Vigar
Miriam Ann
MA
van der Wetering
Sandra
S
Morgan
Brian Paul
BP
Troost
Dirk
D
Baas
Frank
F
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
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