Hydrogen Peroxide and Neutrophil Chemotaxis in a Mouse Model of Bacterial Infection

Neutrophils are an essential protective component of the innate immune system. However, in severe bacterial infections, neutrophils are known to mis-localise from the primary site of infection to other organs, where excessive release of cytokines, chemokines, and neutrophil extracellular traps (NETs) can induce organ damage and death. In this study, we use an animal model of bacterial infection originating in the peritoneum to show that hydrogen peroxide (H2O2, a potent neutrophil chemoattractant) is initially released in high concentrations both in the peritoneum and in multiple ‘off-target’ organs (lungs, liver and kidneys). The initial high H2O2 release inhibits neutrophil chemotaxis, but after 24 h concentrations of H2O2 reduce and can promote neutrophil migration to organs, where they release pro-inflammatory cytokines and chemokines along with NETs. The antimalarial compound artesunate potently inhibits neutrophil migration to off-target organs. It also abolishes cytokine, chemokine, and NET production, suggesting that artesunate may be a valuable novel therapy for preventing off-target organ inflammation associated with severe bacterial infections. Finally, the potency of H2O2 as a chemoattractant is shown by in vitro experiments in which, faced with competing gradients of H2O2 and other chemoattractants, neutrophils preferentially migrate towards H2O2.