ReviewThe complement system in the peripheral nerve: Friend or foe?
Introduction
Complement was discovered in the 1890s (von Fodor, 1887, Nuttall, 1888, Buchner, 1889) as a heat-sensitive serum factor capable of lysing bacteria in the presence of the heat-stable antibody (Bordet, 1895). Molecular biology profoundly transformed our understanding of the complement system and from its original description as “complement” to humoral immunity (Ehrlich and Morgenroth, 1899) today it represents a key component of the innate immune system, defending the host against infections, bridging innate and adaptive immunity and disposing of immune complexes and apoptotic cells (Walport, 2001a, Walport, 2001b). Paradoxically, the same system responsible for such beneficial effects can be deleterious to the host. To prevent complement-mediated tissue injury, over 30 soluble and membrane-bound complement proteins are engaged in a fine coordination of activation and regulation. However, if the regulatory machinery fails, the complement system can contribute to tissue injury and the pathogenesis of various diseases.
The local synthesis of factors and regulators of the complement cascade in the peripheral nerve has been established (de Jonge et al., 2004) but its role in peripheral nerve health, injury and disease remains controversial. Local production of complement factors including regulators of complement activity in the peripheral nerve could protect the healthy nerve from infections. On the other hand, it could erroneously target self tissues. It could facilitate regeneration of injured axons by assisting in the efficient clearance of myelin debris, thought to be inhibitory for axon growth, but it could also exacerbate tissue damage during degeneration hampering the correct regeneration of the nerve. In addition, like it has been proposed for other diseases, complement could contribute to the pathogenesis and progression of neuropathies. Here we will review the evidence supporting the protective and detrimental role of the complement system in the peripheral nerve.
Section snippets
A fine balance of activation and regulation
Activation of the complement system is rapid and efficient. Soluble complement components are present in the blood, body fluids and tissues to readily trigger a defense reaction against external (i.e. pathogens) or internal (i.e. autoimmunity) danger signals (Kohl, 2006). Complement activation can occur via three routes: the classical, the lectin and the alternative pathway. The classical pathway is activated by the recognition of an antigen–antibody complex by C1q. Upon binding, C1r cleaves
Complement as friend
For over 700 million years, the complement system has provided protection against microbial infections (Sunyer et al., 1998), yet its function extends beyond a simple defense mechanism. Today it is clear that the complement system is a key regulator of various stages of an inflammatory reaction. These events are mediated by the potent complement anaphylatoxins C3a and C5a which propagate the immune reaction by binding to their receptors (C3aR, C5aR, C5L2) on the host cell (reviewed by van
Complement as foe
Disruption of the delicate balance between complement activation and regulation is implicated in the pathogenesis, propagation and exacerbation of numerous diseases. Excessive complement activation results from the propagation of an inflammatory reaction or from alterations in the expression and function of complement regulatory proteins.
Complement activation, especially C5a production, plays a major role in the pathogenesis of inflammatory disorders including ischemia/reperfusion injury,
Local synthesis of complement in the peripheral nerve
The primary site of synthesis of plasma complement proteins is liver. Extrahepatic complement biosynthesis occurs in many tissues and it may account for the rapid and efficient ability of the complement system to initiate and propagate an inflammatory response. Local production of complement proteins is especially important in tissues where the access to plasma proteins is hindered by a blood–tissue barrier (Morgan and Gasque, 1997, Laufer et al., 2001).
The brain, shielded by the blood–brain
Complement activation in peripheral nerve degeneration
Transection or crush injury to peripheral nerves results in the disintegration of the axons in the distal stump of the traumatized nerve, a process known as Wallerian degeneration (WD) (Waller, 1850). The initial morphological changes are visible as early as 12 h after injury and include loss of axonal content. Approximately 2–3 days later, the first changes in myelin structure occur. Myelin collapses into ellipsoids in the distal stump and in the most distal end of the proximal stump up to the
Effect of post-traumatic complement activation on peripheral nerve regeneration
Damaged peripheral axons often achieve a good morphological regeneration but regain function slowly and incompletely (Baker et al., 1994, Lundborg and Rosen, 2007). Peripheral nerve regeneration after injury requires axons to re-enter the Schwann cell tubes injured at the lesion site. The search of axons for the appropriate Schwann cell tube is represented by the axonal branches emerging from the tip of the proximal undamaged nerve stump. Once in the distal stump, the axons need to re-navigate
Complement activation in peripheral nerve disease
Activation of the complement system occurs in both chronic and acute diseases of the PNS (Table 3).
Complement regulation in peripheral nerve injury and disease: a therapeutic approach
The implication of complement activation in the initiation, propagation or exacerbation of PNS injury and disease, make it a potential target for therapeutic intervention. A number of complement inhibitors and modulators have been developed and have recently been reviewed by Ricklin and Lambris (2007). Various steps of the proteolytic cascade and its (positive and negative) regulators have been targeted in PNS injury and disease and they are currently in the stage of preclinical development (
Conclusions
It is evident that the complement system plays both a protective and detrimental role in the peripheral nerve. The beneficial effects of complement in immune surveillance and possibly in regulating energy metabolism in the microenvironment of the nerve need to be balanced against the heavy weight of its damaging effects as key determinant of early axon loss and regeneration after injury and in acute PNS diseases. Specific modulation of the complement system at the terminal level of the cascade,
Acknowledgements
We thank Prof. H. Willison for permission to reproduce Fig. 3 and critically reading the manuscript.
References (154)
- et al.
Complement and demyelinating disease: no MAC needed?
Brain Res. Brain Res. Rev.
(2006) - et al.
Role of complement in neurodegeneration and neuroinflammation
Mol. Immunol.
(2007) - et al.
The role of complement in myelin phagocytosis during PNS wallerian degeneration
J. Neurol. Sci.
(1991) - et al.
Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome
Blood
(2006) - et al.
Adipsin and an endogenous pathway of complement from adipose cells
J. Biol. Chem.
(1992) - et al.
Complement factors in adult peripheral nerve: a potential role in energy metabolism
Neurochem. Int.
(2004) - et al.
Acylation stimulating protein (ASP), an adipocyte autocrine: new directions
Semin. Cell Dev. Biol.
(1999) The pathophysiology of hereditary angioedema
Clin. Immunol.
(2005)- et al.
The role of complement in Alzheimer's disease pathology
Biochim. Biophys. Acta
(2000) Pathogenesis of multiple sclerosis
Lancet
(1994)