Complement activation in the injured central nervous system: another dual-edged sword?

Abstract

The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS) function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions.

Figure 1

Common pathways for complement activation. Recognition of antigen-antibody complexes by C1q initiates the ‘classical pathway’. Binding of carbohydrate antigens by mannose-binding lectin (MBL) or MBL-associated serine proteases (MASPs) initiates the ‘lectin pathway’. Both pathways lead to the formation of the C3 convertase, C4b2a. Complement activation through the ‘alternative pathway’ involves the spontaneous hydrolysis of plasma C3, generating a second C3 convertase, C3(H₂O)Bb. Proteolysis of C3 then leads to production of the C3b fragment, which binds to C3 convertases to generate C5 convertases. After the cleavage of C5, the C5b fragment binds C6-C9 to generate the membrane attack complex (MAC). The coagulation cascade leads to complement activation via the ‘extrinsic pathway’; this route does not depend on the presence of C3 convertases. Anaphylatoxins C5a, C3a and C4a are generated through cleavage of C5, C3 and C4, respectively. Soluble and membrane-bound negative regulators of complement and their site of action are indicated in green. The functional significance of certain activation steps is shown in red.

Figure 2

Schematic diagram showing the current understanding of the role of complement activation in the pathophysiology associated with traumatic spinal cord injury (SCI). Mechanical damage to the spinal cord causes neuronal cell death and disruption of the blood-spinal cord barrier (BSB). This primary damage triggers a potent inflammatory response and initiates complement activation. Although complement activation may aid the clearance of cellular debris through opsonisation, it is also known to potentiate injury beyond the site of trauma through e.g. the opsonins C1q, C3b and MAC, which can promote clearance of only mildly compromised cells and thus contribute to secondary demyelination and apoptosis. Known functions of complement in the pathology of SCI are shown in italics; a green font colour indicates a putative reparative role, whereas a red font points towards an injurious role, ¹[93], ²[12], ³[14], ⁴[91], ⁵[16], ⁶[94], ⁷[4,94].