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Nasal colonization by both gram-positive and gram-negative pathogens induces expression of the innate immune protein lipocalin 2 (Lcn2). Lcn2 binds and sequesters the iron-scavenging siderophore enterobactin (Ent), preventing bacterial iron acquisition. In addition, Lcn2 bound to Ent induces release of IL-8 from cultured respiratory cells. As a countermeasure, pathogens of the  Enterobacteriaceae  family such as  Klebsiella pneumoniae  produce additional siderophores such as yersiniabactin (Ybt) and contain the  iroA  locus encoding an Ent glycosylase that prevents Lcn2 binding. Whereas the ability of Lcn2 to sequester iron is well described, the ability of Lcn2 to induce inflammation during infection is unknown. To study each potential effect of Lcn2 on colonization, we exploited  K. pneumoniae  mutants that are predicted to be susceptible to Lcn2-mediated iron sequestration ( iroA ybtS  mutant) or inflammation ( iroA  mutant), or to not interact with Lcn2 ( entB  mutant). During murine nasal colonization, the  iroA ybtS  double mutant was inhibited in an Lcn2-dependent manner, indicating that the  iroA  locus protects against Lcn2-mediated growth inhibition. Since the  iroA  single mutant was not inhibited, production of Ybt circumvents the iron sequestration effect of Lcn2 binding to Ent. However, colonization with the  iroA  mutant induced an increased influx of neutrophils compared to the  entB  mutant. This enhanced neutrophil response to Ent-producing  K. pneumoniae  was Lcn2-dependent. These findings suggest that Lcn2 has both pro-inflammatory and iron-sequestering effects along the respiratory mucosa in response to bacterial Ent. Therefore, Lcn2 may represent a novel mechanism of sensing microbial metabolism to modulate the host response appropriately.

Mucosal Lipocalin 2 Has Pro-Inflammatory and Iron-Sequestering Effects in Response to Bacterial Enterobactin