Mitochondrial C5aR1 activity in macrophages controls IL-1β 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-1β production. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β 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. 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.