Soluble Complement Receptor 1 Protects the Peripheral Nerve from Early Axon Loss after Injury

Abstract

Complement activation is a crucial early event in Wallerian degeneration. In this study we show that treatment of rats with soluble complement receptor 1 (sCR1), an inhibitor of all complement pathways, blocked both systemic and local complement activation after crush injury of the sciatic nerve. Deposition of membrane attack complex (MAC) in the nerve was inhibited, the nerve was protected from axonal and myelin breakdown at 3 days after injury, and macrophage infiltration and activation was strongly reduced. We show that both classical and alternative complement pathways are activated after acute nerve trauma. Inhibition of the classical pathway by C1 inhibitor (Cetor) diminished, but did not completely block, MAC deposition in the injured nerve, blocked myelin breakdown, inhibited macrophage infiltration, and prevented macrophage activation at 3 days after injury. However, in contrast to sCR1 treatment, early signs of axonal degradation were visible in the nerve, linking MAC deposition to axonal damage. We conclude that sCR1 protects the nerve from early axon loss after injury and propose complement inhibition as a potential therapy for the treatment of diseases in which axon loss is the main cause of disabilities.

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.…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…The group found that complement activation in the damaged nerve was almost completely inhibited by sCR1 treatment; deposition of the membrane attack complex was inhibited, as were deposition of C4c (an activation product of the classical complement pathway) and C3c (an activation product common to all complement pathways). The affected nerves were protected from axonal loss and myelin breakdown in the early stages following the trauma, demonstrating the protective capacity of the molecule, however, the effects were relatively short lived, with nerve damage becoming apparent around 7 days after the initial assault (Ramaglia et al 2008). Whether this phenomenon is relevant to AD pathology remains to be established.…”

“…sCR1 is a potent local inhibitor of the classical, lectin and alternative complement pathways (Ramaglia et al 2008). Its mechanism of action appears to be two-fold: firstly, it aids in the dissociation of C3 convertases, and secondly, it targets C3b and C4b for degradation, preventing excessive activation of the complement cascade.…”

“…Its mechanism of action appears to be two-fold: firstly, it aids in the dissociation of C3 convertases, and secondly, it targets C3b and C4b for degradation, preventing excessive activation of the complement cascade. Ramaglia et al looked at the effect of sCR1 treatment on rats with mechanical peripheral nerve crush injuries (Ramaglia et al 2008). The group found that complement activation in the damaged nerve was almost completely inhibited by sCR1 treatment; deposition of the membrane attack complex was inhibited, as were deposition of C4c (an activation product of the classical complement pathway) and C3c (an activation product common to all complement pathways).…”

Uncovering the Path to Neurodegeneration from Playingfield to Battlefield

“…Our effort over the past 10 years has been directed to study the role of the complement cascade in the nervous system [8][9][10][11][12][13][14]. To date we have collected evidence which support a role for complement in microglia priming [8] as well as the protective role of inhibitors of complement activation in nerve damage [10,13].…”