Succinate and inosine coordinate innate immune response to bacterial infection

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-1 beta 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-1 beta and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1 alpha 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.

Automated summary

Macrophages play a role in restricting bacterial infection by promoting phagocytosis and releasing cytokines and complement components. The expression of IL-1 beta and bacterial phagocytosis peak at 8 to 12 hours post-treatment, while the expression of complement component 3 continues to rise for 24 hours. Metabolomic analysis suggests a correlation between cellular concentrations of succinate and IL-1 beta, as well as inosine and C3. Inosine improves the survival of bacterial pathogen-infected mice and tilapia, indicating its potential therapeutic use in preventing and treating bacterial infections.