The Role of the Complement System and the Activation Fragment C5a in the Central Nervous System

The complement system is a pivotal component of the innate immune system which protects the host from infection and injury. Complement proteins can be induced in all cell types within the central nervous system (CNS), where the pathway seems to play similar roles in host defense. Complement activation produces the C5 cleavage fragment C5a, a potent inflammatory mediator, which recruits and activates immune cells. The primary cellular receptor for C5a, the C5a receptor (CD88), has been reported to be on all CNS cells, including neurons and glia, suggesting a functional role for C5a in the CNS. A second receptor for C5a, the C5a-like receptor 2 (C5L2), is also expressed on these cells; however, little is currently known about its potential role in the CNS. The potent immune and inflammatory actions of complement activation are necessary for host defense. However, if over-activated, or left unchecked it promotes tissue injury and contributes to brain disease pathology. Thus, complement activation, and subsequent C5a generation, is thought to play a significant role in the progression of CNS disease. Paradoxically, complement may also exert a neuroprotective role in these diseases by aiding in the elimination of aggregated and toxic proteins and debris which are a principal hallmark of many of these diseases. This review will discuss the expression and known roles for complement in the CNS, with a particular focus on the pro-inflammatory end-product, C5a. The possible overarching role for C5a in diseases of the CNS is reviewed, and the therapeutic potential of blocking C5a/CD88 interaction is evaluated.