The complement cascade: Yin-Yang in neuroinflammation--neuro-protection and -degeneration

Abstract

The complement cascade has long been recognized to play a key role in inflammatory and degenerative diseases. It is a 'double edged' sword as it is necessary to maintain health, yet can have adverse effects when unregulated, often exacerbating disease. The contrasting effects of complement, depending on whether in a setting of health or disease, is the price paid to achieve flexibility in scope and degree of a protective response for the host from infection and injury. Loss or even decreased efficiency of critical regulatory control mechanisms can result in aggravated inflammation and destruction of self-tissue. The role of the complement cascade is poorly understood in the nervous system and neurological disorders. Novel studies have demonstrated that the expression of complement proteins in brain varies in different cell types and the effects of complement activation in various disease settings appear to differ. Understanding the functioning of this cascade is essential, as it has therapeutic implications. In this review, we will attempt to provide insight into how this complex cascade functions and to identify potential strategic targets for therapeutic intervention in chronic diseases as well as acute injury in the CNS.

Fig. 1

Model of complement activation and effector functions. Activation of the complement cascade is initiated by either the classical, lectin, or alternative pathway, but all result in the effector functions of surface opsonization [C3b deposits on the pathogen (yellow) signaling engulfment by a phagocyte], leukocyte recruitment (C3a and C5a), and pathogen lysis by formation and insertion of the C5b-9 complex in membranes (MAC, membrane attack complex) [Permission obtained from Elsevier, (Bohlson et al. 2007)].

Fig. 2

Proposed model for complement-mediated synapse elimination in the developing and diseased CNS. During development, immature astrocytes can promote synapse formation, elimination, and structural plasticity of synaptic circuits via a variety of secreted and contact-dependent signals. (a) In the post-natal CNS, immature astrocytes secrete a signal that up-regulates C1q in neurons. C1q and downstream C3 are then localized to developing synapses and ‘tags’ them for elimination by activated microglia, or via other mechanisms. (b) Complement expression is down-regulated in the healthy adult brain after the appropriate synaptic connections develop into stable, mature synaptic connections. (c) In the damaged or diseased brain, reactive astrocytes (and possibly microglia) re-express C1q and complement cascade proteins, suggesting that the same mechanisms that normally eliminate inappropriate synapses during development are reactivated to trigger destructive synapse loss in the adult CNS.

Fig. 3

Schematic diagram of possible complement-mediated pathogenic mechanisms in CNS lupus.

Fig. 4

Schematic of the two main complement activation pathways showing the outcome of experimental autoimmune encephalomyelitis (EAE) studies using complement mutant mice. Noted in the gray boxes are the specific complement deficient or transgenic mice used in EAE studies and the overall outcome of those studies with respect to disease phenotype. ↔, EAE no different than wildtype controls, ↑, more severe disease than controls, ↓, delayed and/or attenuated disease compared with controls. GFAP, glial fibrillary acidic protein, and astrocyte-specific protein; sCrry, mice producing sCrry in the CNS under the control of a GFAP promoter; MAC, membrane attack complex.