Complement as a powerful "influencer" in the brain during development, adulthood and neurological disorders.

Abstract

The complement system was long considered as only a powerful effector arm of the immune system that, while critically protective, could lead to inflammation and cell death if overactivated, even in the central nervous system (CNS). However, in the past decade it has been recognized as playing critical roles in key physiological processes in the CNS, including neurogenesis and synaptic remodeling in the developing and adult brain. Inherent in these processes are the interactions with cells in the brain, and the cascade of interactions and functional consequences that ensue. As a result, investigations of therapeutic approaches for both suppressing excessive complement driven neurotoxicity and aberrant sculpting of neuronal circuits, require broad (and deep) knowledge of the functional activities of multiple components of this highly evolved and regulated system to avoid unintended negative consequences in the clinic. Advances in basic science are beginning to provide a roadmap for translation to therapeutics, with both small molecule and biologics. Here, we present examples of the critical roles of proper complement function in the development and sculpting of the nervous system, and in enabling rapid protection from infection and clearance of dying cells. Microglia are highlighted as important command centers that integrate signals from the complement system and other innate sensors that are programed to provide support and protection, but that direct detrimental responses to aberrant activation and/or regulation of the system. Finally, we present promising research areas that may lead to effective and precision strategies for complement targeted interventions to promote neurological health.