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

Research output: Contribution to journalReview article

41 Scopus citations


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-celled 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.

Original languageEnglish
Pages (from-to)9-15
Number of pages7
JournalImmunological Reviews
Issue number1
StatePublished - Nov 1 2016


  • C3
  • C3 recycling
  • evolution
  • intracellular complement system

Fingerprint Dive into the research topics of 'Evolution of the complement system: from defense of the single cell to guardian of the intravascular space'. Together they form a unique fingerprint.

  • Cite this