Basophil-derived tumor necrosis factor can enhance immune responses in a sepsis model in mice

Abstract

Abstract Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short lifespan, suggesting that basophils have beneficial roles in maintaining health. However, these roles are not fully defined. Here, we demonstrate that basophil-deficient mice exhibited reduced bacterial clearance, and increased morbidity and mortality, in the cecal ligation and puncture (CLP) model of sepsis. Among the several pro-inflammatory mediators we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. TNF is critical for mounting effective immune responses against certain pathogens. Accordingly, we investigated whether basophil-derived TNF can significantly contribute to the innate immune response triggered by CLP. For this purpose, we generated a conditional mouse in which TNF production was specifically ablated in basophils. Serum and intraperitoneal TNF levels were significantly reduced in mice with genetic ablation of Tnf in basophils after LPS administration, indicating that basophils contribute to increased TNF levels during LPS-induced endotoxemia. Furthermore, mice with basophils deficient in TNF exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality after CLP. Taken together, our studies in mice show that basophils can enhance the innate immune response against bacterial infection and help to prevent sepsis.