The Complement System in Age-Related Neuroinflammation – Fight Aging!
Some fraction of the chronic inflammation of aging derives from maladaptive reactions of the innate immune system to forms of molecular damage. That chronic inflammation then drives changes in cell behavior that lead to tissue dysfunction and structural alteration. All of the common age-related diseases have a strong inflammatory component, and are are accelerated and made worse by greater systemic inflammatory signaling. This is also true of neurodegenerative conditions and the state of inflammation in the brain.
The complement system, best known as a key arm of innate immunity, has gained attention as a major player in healthy central nervous system (CNS) biology based on its contributions to normal neuronal development, but also for its involvement in inflammatory processes within the CNS. Studies have revealed dysregulation of complement activation in various neurodegenerative and inflammatory conditions, including Alzheimer’s disease and multiple sclerosis. Interestingly, both beneficial and pathological activities of complement in the brain or spinal cord are majorly dependent on locally produced complement with limited involvement from the liver-derived circulating complement. This observation is in line with recent adjustments in our understanding of the complement system.
Initially, complement was thought to be a circulation- or vessel-operative system with only a simple role in mediating the detection and removal of bloodborne pathogens. Today, we acknowledge that the complement system is operative at different locations that span the vasculature, the extracellular space in tissues where it is critical in mediating protective tissue immunity, and within cells where it regulates basic cellular processes. The functional reach of complement allows it to directly modulate innate and adaptive immune responses and the behavior of non-immune cells, both during homeostasis and in response to danger-associated molecular patterns (DAMPs) and other noxious triggers. Furthermore, complement has emerged as a key mediator of tissue homeostasis, repair, and regeneration and as such is also involved in the molecular pathways underlying resolution of CNS inflammation and remyelination of neurons after myelin sheath loss, for example, in multiple sclerosis.
Here, we will give a condensed overview of the known sources and roles of complement components in normal CNS function, such as neuronal development and nerve pruning, as well as in disease pathologies contributing to neurodegenerative or neuroinflammatory pathogeneses, and processes that may aid in the resolution or repair of CNS tissue injury. We will conclude with a summary on emerging areas of new complement locations and activities that we suggest could be important in CNS pathologies, such as the intracellularly active complement system and its tight association with the control of single cell physiology and a potential connection between viral infections, complement, and neuroinflammation.
