The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain

The complement cascade is a key component of the innate immune system that is rapidly recruited through a cascade of enzymatic reactions to enable the recognition and clearance of pathogens and promote tissue repair. Despite its well-understood role in immunology, recent studies have highlighted new and unexpected roles of the complement cascade in neuroimmune interaction and in the regulation of neuronal processes during development, aging, and in disease states. Complement signaling is particularly important in directing neuronal responses to tissue injury, neurotrauma, and nerve lesions. Under physiological conditions, complement-dependent changes in neuronal excitability, synaptic strength, and neurite remodeling promote nerve regeneration, tissue repair, and healing. However, in a variety of pathologies, dysregulation of the complement cascade leads to chronic inflammation, persistent pain, and neural dysfunction. This review describes recent advances in our understanding of the multifaceted cross-communication that takes place between the complement system and neurons. In particular, we focus on the molecular and cellular mechanisms through which complement signaling regulates neuronal excitability and synaptic plasticity in the nociceptive pathways involved in pain processing in both health and disease. Finally, we discuss the future of this rapidly growing field and what we believe to be the significant knowledge gaps that need to be addressed.