IL-18 -a Key Modulator of Mucosal Inflammation during Salmonella Infection

Pathogen control at mucosal surfaces relies on an efficient innate immune response. However, the mucosal defense mechanisms are not completely understood. We have analyzed the initial phases of mucosal infection by Salmonella typhimurium (S.Tm) using the streptomycin mouse model. Epithelium-intrinsic recognition of S.Tm was recently shown to rely on the NLRC4/Caspase-1 inflammasome and the shedding of infected enterocytes. However, it had remained unclear if/how inflammasome-activation may activate additional mucosal defenses. In the present study, we show that IL-18, a downstream target of Caspase-1, is required for rapid and efficient stimulation of mucosal inflammation, while IL-1α/β appears dispensable. Knockout mice, cytokine inhibition and cytokine injection revealed that IL-18 accelerates the inflammatory response. IL-18 mediated inflammation was independent of a functional IFNγ response. However, IL-18 facilitated an effective local NK cell response, which was important for a rapid mucosal inflammation. Collectively, these data establish that epithelium-intrinsic NLRC4/Caspase-1 activation orchestrates the shedding of infected enterocytes with mucosal inflammation and implicate IL-18 in the initiation of mucosal inflammation in response to bacterial infection via the induction of an efficient NK cell response.