Critical Roles of Klebsiella pneumoniae Enterobactin in NLRP3 Inflammasome Activation in Airway Epithelial Cells

Abstract

Klebsiella pneumoniae is a ubiquitous Gram-negative bacterium and a common cause of pneumonia, which leads to intense lung injury and mortality that are correlated with deregulated inflammation. Emerging evidence indicates that the NLRP3 inflammasome plays a critical part in regulating inflammatory processes in various infectious diseases. However, its role in K. pneumoniae infections remains elusive. In this study, we identified a siderophore, enterobactin (Ent), from K. pneumoniae as a key factor that induces NLRP3 activation in both the pulmonary epithelial cell line A549 and lung tissue from K. pneumoniae–infected mice. A549 epithelial cells infected with an Ent-deficient mutant (ΔentB) had lower Nlrp3, Asc, and Pro-caspase-1 gene expression, caspase-1 activity, and IL-18 secretion than cells infected with wild-type K. pneumoniae. No such effect was observed with THP-1 macrophages. Ent induced NLRP3 activation and IL-18 production in lung tissue of mice intranasally infected by K. pneumoniae strains. Interestingly, the recruitment of immune cells and production of inflammatory cytokines and chemokines were comparable in wild-type and ΔentB strain–infected mice. Taken together, our findings provide the first example of Ent playing a role in host inflammation control by targeting NLRP3.