Succinate and inosine coordinate innate immune response to bacterial infection

• DOI: 10.1371/journal.ppat.1010796
• Publication Date: 2022-08-26T17:59:21Z
• Authors: Ming Jiang; Zhuang-gui Chen; Hui Li; Tian-tuo Zhang; Man-jun Yang; Xuan-xian Peng; Bo Peng
• Keywords: Lipopolysaccharides; 0301 basic medicine; QH301-705.5; Succinic Acid; Bacterial Infections; RC581-607; Inosine; 3. Good health; Mice; 03 medical and health sciences; Phagocytosis; Animals; Cytokines; Immunologic diseases. Allergy; Biology (General); Research Article

Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat macrophages with LPS and a bacterial pathogen, and demonstrate that expression of cytokine IL-1β and bacterial phagocytosis increase to a transient peak 8 to 12 h post-treatment, while expression of complement component 3 (C3) continues to rise for 24 h post-treatment. Metabolomic analysis suggests a correlation between the cellular concentrations of succinate and IL-1β and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1α through their competitive interactions with prolyl hydroxylase. Furthermore, increased level of inosine in LPS-stimulated macrophages is linked to accumulation of adenosine monophosphate and that exogenous inosine improves the survival of bacterial pathogen-infected mice and tilapia. The implications of these data suggests potential therapeutic tools to prevent, manage or treat bacterial infections.