The role of the complement system in traumatic brain injury: a review

Abstract

Traumatic brain injury (TBI) is an important cause of disability and mortality in the western world. While the initial injury sustained results in damage, it is the subsequent secondary cascade that is thought to be the significant determinant of subsequent outcomes. The changes associated with the secondary injury do not become irreversible until some time after the start of the cascade. This may present a window of opportunity for therapeutic interventions aiming to improve outcomes subsequent to TBI. A prominent contributor to the secondary injury is a multifaceted inflammatory reaction. The complement system plays a notable role in this inflammatory reaction; however, it has often been overlooked in the context of TBI secondary injury. The complement system has homeostatic functions in the uninjured central nervous system (CNS), playing a part in neurodevelopment as well as having protective functions in the fully developed CNS, including protection from infection and inflammation. In the context of CNS injury, it can have a number of deleterious effects, evidence for which primarily comes not only from animal models but also, to a lesser extent, from human post-mortem studies. In stark contrast to this, complement may also promote neurogenesis and plasticity subsequent to CNS injury. This review aims to explore the role of the complement system in TBI secondary injury, by examining evidence from both clinical and animal studies. We examine whether specific complement activation pathways play more prominent roles in TBI than others. We also explore the potential role of complement in post-TBI neuroprotection and CNS repair/regeneration. Finally, we highlight the therapeutic potential of targeting the complement system in the context of TBI and point out certain areas on which future research is needed.

Complement activation contributes to perioperative neurocognitive disorders in mice

“…Under pathological conditions, excessive hippocampal C3 deposition has been implicated in the development of many neurological disorders [13, 14]. In the current model, we found an early and significant elevation of hippocampal C3 levels after orthopedic surgery, supporting the involvement of complement activation in the pathophysiology of PND.…”

Complement factor C1q mediates chronic neuron loss and inflammation post-brain injury

“…We chose to test the importance of one specific inflammatory pathway, the classical complement pathway, using a pharmacological tool to block C1q in TBI mice. C1q has a well-documented role in normal brain function such as synaptic pruning during development (24), as well as its 405 involvement in several neurological diseases (16)(17)(18)(19)(20)(21)(22). In addition, we had observed that C1q expression was highly increased in the corticothalamic circuit for up to four months after TBI ( Figure S2).…”

Does Complement-Mediated Hemostatic Disturbance Occur in Traumatic Brain Injury? A Literature Review and Observational Study Protocol

“…The complement system is part of the innate immune response [59,60] and consists of serine proteases that are encoded from the same ancestral genes as coagulation proteins [61]. It functions as a form of intravascular surveillance that, when activated, amplifies and forms the complement cascade.…”