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

Description Mitochondrial C5aR1 signaling is required for proinflammatory macrophage activity during crystal-induced sterile inflammation. Complement coordinates inflammation in macrophages The serum complement system performs well-established functions in innate immune system recognition and destruction of invading pathogens, but complement proteins produced by immune cells can also execute distinct functions intracellularly. In human macrophages, Niyonzima et al. demonstrate that the complement protein C5a signals on mitochondrial membranes through its receptor C5aR1 to control IL-1β production in response to cholesterol crystal (CC) uptake. C5a/C5aR1 signaling altered mitochondrial activity and increased reactive oxygen species production, promoting IL-1β gene expression and processing. In a mouse model of atherosclerosis, in which CC accumulates in arterial walls, deletion of C5aR1 in myeloid cells reduced the severity of cardiovascular disease. These results identify a function for intracellular complement proteins in myeloid cell mitochondrial metabolism and responses to 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 nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. 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 the 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 contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.