Evolution of the complement system: from defense of the single cell to guardian of the intravascular space

Abstract

The complement system is an evolutionarily ancient component of immunity that revolves around the central component C3. With the recent description of intracellular C3 stores in many types of human cells, our view of the complement system has expanded. In this article, we hypothesize that a primitive version of C3 comprised the first element of the original complement system and initially functioned intracellularly and on the membrane of single-cell organisms. With increasing specialization and multicellularity, C3 evolved a secretory capacity that allowed it to play a protective role in the interstitial space. Upon development of a pumped circulatory system, C3 was synthesized in large amounts and secreted by the liver to protect the intravascular space. Recent discoveries of intracellular C3 activation, a C3-based recycling pathway and C3 being a driver and programmer of cell metabolism suggest that the complement system utilizes C3 to guard not only extracellular but also the intracellular environment. We predict that the major functions of C3 in all four locations (i.e., intracellular, membrane, interstitium and circulation) are similar: opsonization, membrane perturbation, triggering inflammation and metabolic reprogramming.

Keeping It All Going—Complement Meets Metabolism

“…In conjunction with the discoveries of new sites of action (intracellularly) and strong indication that complement also partakes in general basic cell physiology, our perception of this ancient immune surveillance system is now changing. Complement was initially discovered as a serum-active system and was ever since known as the first line of defense against pathogen- and self-derived dangers detected in blood and other body fluids (10, 90). However, the existence of a complosome and its direct ability to regulate cell metabolism suggests that complement may have functioned originally as an intracellular sensor system and only became a secreted and “systemic” system when life evolved from single cell to multicell and then to multitissue/organ organisms .…”

Complement in cancer: untangling an intricate relationship

“…Unconventional routes of complement activation include the deployment of proteolytic enzymes of the coagulation and fibrinolytic systems that can efficiently cleave both C3 and C5 into their bioactive fragments 130 . These non-canonical routes of activation, in conjunction with the intracellular complement circuitry 38,131 , define a broader pathophysiological base of triggering cues that can initiate homeostatic or disease-tailored complement responses.…”

The Role of Complement in Liver Injury, Regeneration, and Transplantation

“…Hepatocytes synthesize most of the components, and the liver accounts for up to 90% of the fluid‐phase complement proteins . It is hypothesized that the first complement component (i.e., C3) early in evolution was expressed intracellularly and that when organisms evolved into more complex bodies, complement proteins began to be secreted into the intercellular space and were later allocated for hepatic synthesis for intravascular release …”