Complement inhibition accelerates regeneration in a model of peripheral nerve injury.
Complement (C) activation is a crucial event in peripheral nerve degeneration but its effect on the subsequent regeneration is unknown. Here we show that genetic deficiency of the sixth C component, C6, accelerates axonal regeneration and recovery in a rat model of sciatic nerve injury. Foot-flick test and Sciatic Function Index monitored up to 5 weeks post-injury showed a significant improvement of sensory and motor function in the C6 deficient animals compared to wildtypes. Retrograde tracing experiments showed a significantly higher number of regenerated neurons at 1 week post-injury in C6 deficient rats than wildtypes. Pathology showed improved nerve regeneration in tibials of C6 deficient animals compared to wildtypes. Reconstitution with purified human C6 protein re-established the wildtype phenotype whereas pharmacological inhibition of C activation with soluble C receptor 1 (sCR1) facilitated recovery and improved pathology similarly to C6 deficient animals. We suggest that a destructive C-mediated event during nerve degeneration hampers the subsequent regenerative process. These findings provide a rationale for the testing of anti-complement agents in human nerve injury.
Ramaglia
Valeria
V
Neurogenetics Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Tannemaat
Martijn Rudolf
MR
de Kok
Maryla
M
Wolterman
Ruud
R
Vigar
Miriam Ann
MA
King
Rosalind Helen Mary
RH
Morgan
Bryan Paul
BP
Baas
Frank
F
D000818:Animals; D003167:Complement Activation / Q000276:immunology; D003183:Complement C6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006461:Hemolysis / Q000276:immunology; D006801:Humans; D009416:Nerve Regeneration / Q000235:genetics / Q000276:immunology*; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000276:immunology* / Q000503:physiopathology / Q000648:ultrastructure; D051381:Rats; D011951:Receptors, Complement / Q000097:blood / Q000276:immunology; D020127:Recovery of Function
D003183:Complement C6; D011951:Receptors, Complement; C082885:soluble complement inhibitor 1