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.

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

“…It is not known how natural antibodies enter the PNS and whether they recognize specific peripheral nerve antigens. In acute nerve injury, depletion of complement or the membrane attack complex decreases macrophage activation (18,19). Similarly, in our study, mSOD1C4Ϫ/Ϫ mice showed significantly decreased macrophage levels and activation.…”

“…S5b). Following symptom onset (week 12), hypertrophic microglia was observed throughout the gray and white matter, peaking in activation at end stage (week 19). Flow cytometry demonstrated a similar time course, with mSOD1 G93A microglia showing population-wide shifts in surface activation markers CD11c and CD86 after symptomatic onset (Fig.…”

“…At presymptomatic time points (i.e., weeks 9-12), focal activation occurs for PNS macrophages and spinal cord microglia. Following clinical onset (i.e., weeks [12][13][14][15][16][17][18][19], activation of innate immunity becomes widespread in both tissues as indicated by FACS and histological analysis.…”

“…Humoral system components, including circulating antibodies and complement, are known to deposit in the ALS spinal cord, and may play significant roles in damaging motor neurons (6,17). In acute PNS injury, complement mediates the opsonization of myelin debris and recruitment of myeloid cells (18,19). Therefore, we analyzed the role of the humoral immune system in the PNS of ALS Tg mice.…”

C3-dependent mechanism of microglial priming relevant to multiple sclerosis

“…Primed microglia in Crry −/− likely respond more quickly and more vigorously to the immunization challenge; indeed, levels of the inflammatory cytokine IL-1β in Crry −/− spinal cord at death were markedly elevated compared with WT levels. We have previously shown that axonal injury, an early event in EAE, activates complement (39)(40)(41), providing the additional drive to microglial activation, production of neurotoxic mediators, and destruction of axons and myelin.…”