Figure 8.

The evolution of complement from an intracellular driver of cell homeostasis and effector function to a serum sentinel system orchestrating host integrity. The ancient origin of complement and its coevolution and tight connection with basic cellular processes suggest that complement may have originally appeared as an intracellular system regulating single-cell homeostasis and may have functioned to mostly recognize and rectify danger derived from the self/within the cell (left). When life evolved into multicellular organisms, complement also became a secreted system and adopted an additional function of being a protector of the extracellular space against pathogens (right). Today, this dual role of complement likely explains why this ancient system in direct intra- and extracellular cross talk with other sensor and effector systems (such as TLRs, inflammasomes, and growth factors; not shown here) has such profound effects on normal cell and host function in immunity and beyond. Circles with solid outlines depict functions for complement that have been clearly demonstrated, whereas circles with dashed outlines are processes that we anticipate complement will contribute to. For many of the activities currently solely attributed to the liver-derived, extracellular complement, possible contributions from the intracellular complement system, the complosome, have not yet been assessed.