Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation.
Nathalie NiyonzimaJubayer RahmanNatalia KunzErin E WestTilo FreiwaldJigar V DesaiNicolas S MerleAlexandre GidonBjørnar SporsheimMichail S LionakisKristin EvensenBeate LindbergKarolina SkagenMona SkjellandParul SinghMarkus HaugMarieta M RusevaMartin KolevJack BibbyOlivia MarshallBrett A O'BrienNigel DeeksBehdad AfzaliRichard J ClarkTrent M WoodruffMilton PryorZhi-Hong YangAlan T RemaleyTom Eirik MollnesStephen M HewittBingyu YanMajid KazemianMáté G KissChristoph J BinderBente HalvorsenTerje EspevikClaudia KemperPublished in: Science immunology (2021)
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.
Keyphrases
- oxidative stress
- reactive oxygen species
- cardiovascular disease
- induced apoptosis
- single cell
- dendritic cells
- cell therapy
- adipose tissue
- end stage renal disease
- diabetic rats
- cell cycle arrest
- gene expression
- bone marrow
- rheumatoid arthritis
- transcription factor
- ejection fraction
- acute myeloid leukemia
- genome wide
- cell death
- type diabetes
- physical activity
- peritoneal dialysis
- immune response
- regulatory t cells
- machine learning
- endothelial cells
- drug delivery
- mesenchymal stem cells
- coronary artery disease
- pi k akt
- patient reported outcomes
- weight loss
- heat shock
- cardiovascular events
- type iii