Activation of the complement system and its functions
The activation of the complement system and its functions. (A) Complement from the liver into circulation can be activated via three canonical pathways, namely classical, lectin, and alternative. All three pathways lead to the formation of C3 and C5 convertases. C3 convertase cleaves C3 into biologically active C3a and C3b, and C5 convertase cleaves C5 into biologically active C5a and C5b. The C5b fragments initiate the formation of the membrane attack complex (MAC), which functions to cause osmotic lysis. Other complement component functions include C3b acting as an opsonin, while C3a and C5a anaphylatoxins induce inflammation via C3aR and C5aR, respectively. (B) Cells can secrete C3 and C5 components to the extracellular space, where they get activated by C3 and C5 convertases, respectively. The activated fragments, C3a and C5a, can signal via their respective receptors to induce NLRP3 inflammasome formation and cytokine release. Stimulation of the CD46 receptor can activate intracellular C5, allowing C5a–C5aR1 signaling to induce the production of reactive oxygen species (ROS) rnd NLRP3 assembly [66]. Intracellular C3 ban regulate autophagy by binding to autophagy-related protein 16-1 (ATG16L1) [67]. Intracellular complement activation can also occur in subcellular compartments. In lysosomes, cathepsin L (CTSL) and cathepsin (CTSD) can activate C3 and C5, respectively, to promote cell survival and tumorigenesis [55,57]
