Cell-intrinsic complement C3 suppresses IFN-β production in macrophages

The cell-intrinsic complement system plays a crucial role in regulating cell-physiological processes, with complement components interacting with intracellular effector systems to modulate responses to pathogens or harmful stimuli. In a recent study, researchers explored whether cell-intrinsic C3 influences inflammatory responses in macrophages.

Upon examining LPS-stimulated C3 knockout THP-1-derived macrophages, they found that IFN-β production was significantly heightened, alongside a rise in interferon-stimulated gene expression and increased secretion of IFN-induced cytokines and chemokines. Upon further analysis, C3-deficient cells exhibited elevated phosphorylation of IRF3 at Ser396 and a more stable interaction between IRF3 and TBK1.

This resulted in enhanced IRF3 dimerization and nuclear translocation. Notably, TBK1 phosphorylation remained unchanged, suggesting that C3 primarily restricts IRF3-TBK1 complex formation rather than the initial TBK1 activation. The researchers also discovered that small-molecule inhibitors of complement factors B and D could restore full-length C3 abundance in LPS-stimulated primary human macrophages, leading to a decrease in LPS-induced IFN-β production.

These findings demonstrate that full-length, uncropped C3 suppresses IFN-β production in human macrophages, emphasizing the significance of the cell-intrinsic complement system in fine-tuning inflammatory responses to pathogens.