Mitochondrial C5aR1 activity in macrophages controls IL-1ß production underlying sterile inflammation

While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the 'complosome', functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also non-redundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and can generate autocrine C5a via formation of an intracellular C5 convertase. Further, cholesterol crystal-sensing by macrophages induces C5aR1 signaling on mitochondrial membranes, which shifts ATP production via reverse electron chain flux towards reactive oxygen species (ROS) production and anaerobic glycolysis to favor IL-1ß production. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1ß produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a novel contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis. Overall design: Four atherosclerosis patients are recuited in this study. The biopsies containing atherosclerotic plaques of each patient were split into macroscopically equal pieces and treated with non-cell permeable C5aR1 antagonist PMX53 (10 µg/ml), cell permeable C5aR1 antagonist JEP1375 (10 µg/ml) or PBS for 6 hrs.