Fig. 1.

Immunometabolites succinate and itaconate are released during airway macrophage infection. a During homeostasis, airway macrophages employ the TCA cycle and OXPHOS to generate energy (ATP) in the mitochondria. In these conditions, the pro-inflammatory transcription factor HIF1α is inhibited in the cytoplasm by prolylhydroxylases (PHD). b Upon bacterial LPS detection by toll-like receptor 4 (TLR4), cells exhibit metabolic reprograming. Mitochondria become a major source for reactive oxygen species (ROS), which is mostly derived from succinate accumulation and its oxidation by succinate dehydrogenase (SDH). Succinate and ROS inhibits PHD, which release HIF1α to promote transcription of pro-inflammatory cytokines like IL-1β. Glycolysis becomes the major ATP source. c To avoid excessive tissue oxidation, macrophages also upregulate Immunoresponsive Gene 1 (IRG1), which synthetizes the SDH and KEAP1 inhibitor itaconate. SDH blockade induces succinate accumulation, which is excreted from the cell together with itaconate. Reduced SDH function by IRG1 regulates airway HIF1α and IL-1β activity. Itaconate is bactericidal