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-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.

Keywords: C3; C3 recycling; evolution; intracellular complement system.

Figure 1. Alternative pathway activation and amplification

nC3, native C3; AL, amplification loop; FB, Factor B; FD, Factor D.

Figure 2. Steps in the evolution of the complement system

Four environments that C3 adapted to function in to defend the evolving host.

Figure 3. Functions of C3

C3 activation produces C3b and C3a. C3b amplifies the cascade through the AP amplification loop, is an opsonin and leads to cell lysis. C3a is an inflammatory mediator.

Figure 4. C3a and C3aR are intracellular and translocate and colocalize upon CD4⁺ T cell activation

Non-activated or anti-CD3 and anti-CD46 activated human peripheral blood CD4⁺ T cells were permeabilized and stained for C3a (red) and C3aR (green). Two representative examples of the migration of C3a and C3aR to the plasma membrane upon activation of human CD4⁺ T cells (right hand panel). Adapted from (14).

Figure 5. C3(H₂O) recycling pathway

C3(H₂O) is continuously internalized by cells and a majority returned to the extracellular milieu. Under steady state conditions, a fraction of the C3(H₂O) is metabolized intracellularly. Loaded FH (61) and FI (unpublished observation) act on the C3(H₂O), resulting in iC3(H₂O). Multiple intracellular proteases could also cleave the C3(H₂O) and iC3(H₂O) releasing C3a and likely other active fragments. The C3a and C3aR could be engaged to signal intracellularly, on the membrane, or in the interstitial space. R; receptor.

Figure 6. Functions of C3(H₂O) by location

Intracellular C3(H₂O) is a source of C3a that could then engage the C3aR, it is secreted and C3 fragments are generated by cofactor activity, some of which contain C3a. Extracellular C3(H₂O) is regulated by cofactor activity, taken up into cells and initiates the AP.