title: Macrophagic control of the response to uropathogenicE. coliinfection by regulation of iron retention in an IL-6-dependent manner.
abstract: UropathogenicEscherichia coli(UPEC), the causative agent of over 85% of urinary tract infections (UTIs), elaborate a number of siderophores to chelate iron from the host. On the other hand, the host immune imperative is to limit the availability of iron to the bacteria. Little is known regarding the mechanisms underlying this host-iron-UPEC interaction. Our objective was to determine whether macrophages, in response to UPEC infection, retain extracellular siderophore-bound and free iron, thus limiting the ability of UPEC to access iron.
  
  
  
  Quantitative PCR, immunoblotting analysis, and gene expression analysis of wild type and IL-6-deficient macrophages was performed.
  
  
  
  We found that (1) macrophages upon UPEC infection increased expression of lipocalin 2, a siderophore-binding molecule, ofDmt1, a molecule that facilitates macrophage uptake of free iron, and of the intracellular iron cargo molecule ferritin, and decreased expression of the iron exporter ferroportin; (2) bladder macrophages regulate expression of genes involved in iron retention upon UPEC infection; (3) IL-6, a cytokine known to play an important role in regulating host iron homeostasis as well as host defense to UPEC, regulates this process, in part by promoting production of lipocalin 2; and finally, (4) inhibition of IL-6 signaling genetically and by neutralizing antibodies against the IL-6 receptor, promoted intra-macrophagic UPEC growth in the presence of excess iron.
  
  
  
  Together, our study suggests that macrophages retain siderophore-bound and free iron in response to UPEC and IL-6 signaling is necessary for macrophages to limit the growth of UPEC in the presence of excess iron. IL-6 signaling and iron regulation is one mechanism by which macrophages may mediate UPEC clearance.
authors.affiliation: Department of Obstetrics and Gynecology Washington University School of Medicine St. Louis Missouri.
authors.forename: Nana
authors.initials: N
authors.lastname: Owusu-Boaitey
authors.affiliation: Department of Obstetrics and Gynecology Washington University School of Medicine St. Louis Missouri.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Bauckman
authors.affiliation: Department of Obstetrics and Gynecology Washington University School of Medicine St. Louis Missouri.
authors.forename: Tingxuan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and GynecologyWashington University School of MedicineSt. LouisMissouri; Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisMissouri.
authors.forename: Indira U
authors.initials: IU
authors.lastname: Mysorekar
mesh_terms: D000818:Animals; D004927:Escherichia coli Infections / Q000276:immunology*; D029968:Escherichia coli Proteins; D015850:Interleukin-6 / Q000502:physiology*; D007501:Iron / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017262:Siderophores; D015398:Signal Transduction; D014552:Urinary Tract Infections; D056689:Uropathogenic Escherichia coli / Q000472:pathogenicity*
chemical_list: D029968:Escherichia coli Proteins; D015850:Interleukin-6; D017262:Siderophores; D007501:Iron
keywords: Ferritin; lipocalin 2; urinary tract infection