Interleukin-8 Secretion in Response to Aferric Enterobactin Is Potentiated by Siderocalin

Abstract

Siderophores are low-molecular-weight iron chelators secreted by microbes to obtain iron under deprivation. We hypothesized that the catecholate siderophore enterobactin, produced by Enterobacteriaceae, serves as a proinflammatory signal for respiratory epithelial cells. Respiratory tract responses were explored, since at this site siderocalin, an enterobactin-binding mammalian gene product, is expressed inducibly at high levels and enterobactin-secreting respiratory flora is rare, suggesting selection against a dependence on enterobactin. Addition of aferric, but not iron-saturated, enterobactin elicits a dose-dependent increase in secretion of the proinflammatory chemokine interleukin-8 by human respiratory epithelial cells in culture. This response to purified enterobactin is potentiated by recombinant siderocalin at physiologically relevant concentrations. Conditioned media from genetically modified Escherichia coli strains expressing various levels of enterobactin induce an enterobactin-mediated proinflammatory response. Siderocalin has been shown to deliver enterobactin to other mammalian cell types, exogenously supplied siderocalin can be detected within epithelial cells, and siderocalin increases delivery of enterobactin to the intracellular compartment. Although many siderophores perturb labile cellular iron pools, only enterobactin elicits interleukin-8 secretion, suggesting that iron chelation is necessary but not sufficient. Thus, aferric enterobactin may be a proinflammatory signal for respiratory epithelial cells, permitting detection of microbial communities that have disturbed local iron homeostasis, and siderocalin expression by the host amplifies this signal. This may be a novel mechanism for the mucosa to respond to metabolic signals of expanding microbial communities.

α–Intercalated cells defend the urinary system from bacterial infection

“…83, 109, 110), markedly limited the expression of Lcn2, it did not abolish its expression. Exciting preliminary observations indicated that Ent can stimulate cytokine expression in a cell line (111) and LCN2 expression in mice (Supplemental Figure 4). This is an intriguing finding, because it would suggest that a specific defense (LCN2) is activated by its own cognate bacterial ligand (Ent).…”

Specific Roles of the iroBCDEN Genes in Virulence of an Avian Pathogenic Escherichia coli O78 Strain and in Production of Salmochelins

“…However, since iro gene clusters have been shown to be present in multiple copies in certain E. coli strains, the possibility that there are additional copies of iro genes, including an iroE ortholog, within certain K. pneumoniae strains cannot be excluded. The importance of salmochelins as newly discovered siderophores that are able to evade the mammalian innate immune response protein NGAL (lipocalin 2 and siderocalin) has been revelatory for furthering our understanding of the role of the enterobactin pathway as a precursor required for the generation of these glucosylated virulence factors (18,27) and the importance of NGAL as a host response protein that plays a critical role in host protection from certain bacterial infections and possibly detection of enterobactin (19,22,40). In the avian host, it is clear from our study that the enterobactin system alone is insufficient for APEC virulence, and it is thus probable that an avian host defense protein akin to NGAL plays a similar role in protection against enterobactin-mediated iron acquisition.…”

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

“…Upon analysis of the published LCN2 promoter (21) we noticed NF-κB binding sites, but also glucocorticoid response elements and several binding sites for transcription factors critically involved in the polarization of M2 macrophages (22), such as STAT3, CREB, and C/EBPβ. Considering that LCN2 may modu-late inflammation (23,24), we hypothesized that LCN2 can play a role in macrophage polarization and thereby affect the host defense against pathogens such as S. pneumoniae.…”