Augmented bacterial elimination by Kupffer cells after IL-18 pretreatment via IFN-γ produced from NK cells in burn-injured mice

We recently demonstrated that IL-18 injections following burn restored IFN-γ production and increased mouse survival after bacterial infection. However, it has yet to be fully elucidated how the IL-18 therapy affects the function of phagocytic cells. We investigated the effect of IL-18 therapy on function and interaction of Kupffer cells and NK cells in burned mice. C57BL/6 mice received a 20% full-thickness burn, followed by multiple injections with IL-18. Although burn-injured mice had decreased expression of IL-18 receptors on the NK/NKT cells 5 days after injury, multiple IL-18 injections restored this expression. IL-18 treatment also augmented Kupffer cell phagocytosis. Although burn decreased the number of CD68+ Kupffer cells with phagocytic activity, IL-18 treatment partially restored their proportion, and augmented phagocytosis-induced ROS production in CD68+ Kupffer cells after the injection of heat-killed Escherichia coli. Consistently, IL-18 restored the impaired E. coli killing activity of Kupffer cells of burn-injured mice. Such Kupffer cell activation by IL-18 was abrogated by the deletion of NK cells or IFN-γ. In conclusion, IL-18 therapy in burn-injured mice enhanced function of CD68+ Kupffer cells via the activation of liver NK cells and augmentation of their IFN-γ production, thereby improving survival after E. coli infection.