The membrane attack complex as an inflammatory trigger

The final common pathway of all routes of complement activation involves the non-enzymatic assembly of a complex comprising newly formed C5b with the plasma proteins C6, C7, C8 and C9. When assembly occurs on a target cell membrane the forming complex inserts into and through the bilayer to create a pore, the membrane attack complex (MAC). On some targets, pore formation causes rapid lytic destruction; however, most nucleated cell targets resist lysis through a combination of ion pumps, membrane regulators and active recovery processes. Cells survive but not without consequence. The MAC pore causes ion fluxes and directly or indirectly impacts several important signalling pathways that in turn activate a diverse series of events in the cell, many of which are highly pro-inflammatory. Although this non-lytic, pro-inflammatory role of MAC has been recognised for thirty years, no consensus signalling pathway has emerged. Recent work, summarised here, has implicated specific signalling routes and, in some cells, inflammasome involvement, opening the door to novel approaches to therapy in complement-driven pathologies.