Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia
Kathryn R. Michels, … , Tomas Ganz, Borna Mehrad
Kathryn R. Michels, … , Tomas Ganz, Borna Mehrad
Published March 23, 2017
Citation Information: JCI Insight. 2017;2(6):e92002. https://doi.org/10.1172/jci.insight.92002.
View: Text | PDF
Research Article Infectious disease Inflammation

Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia

  • Text
  • PDF
Abstract

Gram-negative pneumonia is a dangerous illness, and bacterial dissemination to the bloodstream during the infection is strongly associated with death. Antibiotic resistance among the causative pathogens has resulted in diminishing treatment options against this infection. Hepcidin is the master regulator of extracellular iron availability in vertebrates, but its role in the context of host defense is undefined. We hypothesized that hepcidin-mediated depletion of extracellular iron during Gram-negative pneumonia protects the host by limiting dissemination of bacteria to the bloodstream. During experimental pneumonia, hepcidin was induced in the liver in an IL-6–dependent manner and mediated a rapid decline in plasma iron. In contrast, hepcidin-deficient mice developed a paradoxical increase in plasma iron during infection associated with profound susceptibility to bacteremia. Incubation of bacteria with iron-supplemented plasma enhanced bacterial growth in vitro, and systemic administration of iron to WT mice similarly promoted increased susceptibility to bloodstream infection. Finally, treatment with a hepcidin analogue restored hypoferremia in hepcidin-deficient hosts, mediated bacterial control, and improved outcomes. These data show hepcidin induction during pneumonia to be essential to preventing bacterial dissemination by limiting extracellular iron availability. Hepcidin agonists may represent an effective therapy for Gram-negative infections in patients with impaired hepcidin production or signaling.

Authors

Kathryn R. Michels, Zhimin Zhang, Alexandra M. Bettina, R. Elaine Cagnina, Debora Stefanova, Marie D. Burdick, Sophie Vaulont, Elizabeta Nemeth, Tomas Ganz, Borna Mehrad

×

Figure 1

Iron availability during Klebsiella pneumonia.

Options: View larger image (or click on image) Download as PowerPoint
Iron availability during Klebsiella pneumonia.
Time 0 represents uninfec...
Time 0 represents uninfected animals. (A) Iron concentration in the plasma. (B and C) Calculated total iron levels in whole lung homogenate per mouse, and bronchoalveolar lavage fluid (BAL) recovered in a volume of 1 ml per mouse. Data shown as mean ± SE; n = 4–6 animals per time point, representative of 2 independent experiments; ***P < 0.001 (1-way ANOVA, multiple comparison for linear trend). (D) Plasma iron following i.p. injection with PBS or ferric ammonium citrate (iron) 30 minutes prior to intrapulmonary K. pneumoniae challenge. n = 6–8 per group per time point, combined result of 2 experiments; ****P < 0.0001, two-way ANOVA. (E) Mice were treated with either PBS or ferric ammonium citrate (iron) 30 minutes prior to intrapulmonary K. pneumoniae challenge and again 24 hours thereafter. n = 6–12 per group, combined result of 2 experiments; ***P < 0.001 Mantel-Cox test. (F) Bacterial burden on day 2 of infection in mice treated with ferric ammonium citrate or PBS prior to intratracheal challenge with K. pneumonia. Horizontal lines represent median, and each circle represents 1 animal; animals with no detectable bacteria are reported to have a bacterial burden of 1 CFU on the logarithmic scale. n = 9–11, combined result of 2 experiments; **P < 0.01 Mann-Whitney U test.

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts