The multifaceted impact of complement on atherosclerosis

As one of the cornerstones of innate immunity, the complement system has long been implicated in the pathogenesis of atherosclerosis. Growing evidence demonstrates the presence of complement activation products in human atherosclerotic plaques, where they can exhibit both protective and proatherogenic properties as supported by numerous experimental findings. While complement initiation resulting in the cleavage of the central complement component C3 appears to have a crucial role in tempering lesion progression by aiding the clearance of apoptotic cells, cascade propagation to the terminal pathway characterized by C5 cleavage and membrane attack complex formation may promote plaque vulnerability. Nevertheless, these assumptions are made based on studies focusing predominantly on systemic, liver-derived complement, whereas it is now evident that almost every cell type can produce complement proteins and the site of synthesis can dictate the function of complement. However, the role of local complement activation in lesion formation remains largely understudied. Here, we review the current literature on complement activation in human atherosclerotic plaques, discuss clinical and genetic associations between complement and cardiovascular disease susceptibility and summarize experimental evidence gained from animal studies. Furthermore, by highlighting recent findings with respect to extrahepatic complement production in the artery wall, we illustrate the necessity to uncover the contribution of local (paracrine, autocrine as well as intracellular) vis-à-vis systemic complement activation to atherosclerotic lesion formation.