Intracellular complement: Evidence, definitions, controversies, and solutions

The term "intracellular complement" has been introduced recently as an umbrella term to distinguish functions of complement proteins that take place intracellularly, rather than in the extracellular environment. However, this rather undefined term leaves some confusion as to the classification of what intracellular complement really is, and as to which intracellular compartment(s) it should refer to. In this review, we will describe the evidence for both canonical and non-canonical functions of intracellular complement proteins, as well as the current controversies and unanswered questions as to the nature of the intracellular complement. We also suggest new terms to facilitate the accurate description and discussion of specific forms of intracellular complement and call for future experiments that will be required to provide more definitive evidence and a better understanding of the mechanisms of intracellular complement activity.