Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis

Abstract

The immune response after brain injury is highly complex and involves both local and systemic events at the cellular and molecular level. It is associated to a dramatic over-activation of enzyme systems, the expression of proinflammatory genes and the activation/recruitment of immune cells. The complement system represents a powerful component of the innate immunity and is highly involved in the inflammatory response. Complement components are synthesized predominantly by the liver and circulate in the bloodstream primed for activation. Moreover, brain cells can produce complement proteins and receptors. After acute brain injury, the rapid and uncontrolled activation of the complement leads to massive release of inflammatory anaphylatoxins, recruitment of cells to the injury site, phagocytosis and induction of blood brain barrier (BBB) damage. Brain endothelial cells are particularly susceptible to complement-mediated effects, since they are exposed to both circulating and locally synthesized complement proteins. Conversely, during neurodegenerative disorders, complement factors play distinct roles depending on the stage and degree of neuropathology. In addition to the deleterious role of the complement, increasing evidence suggest that it may also play a role in normal nervous system development (wiring the brain) and adulthood (either maintaining brain homeostasis or supporting regeneration after brain injury). This article represents a compendium of the current knowledge on the complement role in the brain, prompting a novel view that complement activation can result in either protective or detrimental effects in brain conditions that depend exquisitely on the nature, the timing and the degree of the stimuli that induce its activation. A deeper understanding of the acute, subacute and chronic consequences of complement activation is needed and may lead to new therapeutic strategies, including the ability of targeting selective step in the complement cascade.

Critical Role and Therapeutic Control of the Lectin Pathway of Complement Activation in an Abortion-Prone Mouse Mating

“…Activation of the lectin pathway has been implicated in tissue damage associated with ischemia reperfusion of several organs and tissues including myocardium, gastrointestinal tract, skeletal muscles, and brain (27,28). The results of this study indicate that the lectin pathway activation is also involved in the adverse pregnancy outcome observed in DBA/2-mated CBA/J.…”

Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells

“…The complement system mediates immune responses to inflammatory triggers to attract additional phagocytes, enhances the ability of phagocytic cells to clear microbes and damaged cells, and precipitates lysis of foreign microbes via the membrane attack complex (MAC) (Janeway, Travers et al 2001, Sarma and Ward, 2011). However, inappropriate complement activation can also cause cell injury or death and has been recognized as an important pathogenic factor in many diseases including neurodegenerative diseases such as AD (Crehan et al, 2012; Orsini et al, 2014). The gene expression of CFB and C3 were upregulated 266 and 12-fold, respectively, in the LPS/ IFNγ-activated microglial cells compared to the controls.…”

Complement C3 Expression Is Decreased in Autism Spectrum Disorder Subjects and Contributes to Behavioral Deficits in Rodents

“…In traumatic brain injury, it has been shown that the majority of complement proteins in the brain are from the periphery due to the dysfunction of the BBB [34]. A number of studies suggest mast cell activation as a mechanism for BBB disruption and brain inflammation in ASD [35,36]. However, further studies are warranted to better understand the brain versus peripheral contribution of the complement system in ASD.…”