Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Collagen VI Contains Multiple Host Defense Peptides with Potent In Vivo Activity

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Multiple Homozygous Variants in the STING-Encoding TMEM173 Gene in HIV Long-Term Nonprogressors

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Gayathri Srinivasan
  • Jesse D Aitken
  • Benyue Zhang
  • Frederic A Carvalho
  • Benoit Chassaing
  • Rangaiah Shashidharamurthy
  • Niels Borregaard
  • Dean P Jones
  • Andrew T Gewirtz
  • Matam Vijay-Kumar
Vis graf over relationer
Various states of inflammation, including sepsis, are associated with hypoferremia, which limits iron availability to pathogens and reduces iron-mediated oxidative stress. Lipocalin 2 (Lcn2; siderocalin, 24p3) plays a central role in iron transport. Accordingly, Lcn2-deficient (Lcn2KO) mice exhibit elevated intracellular labile iron. In this study, we report that LPS induced systemic Lcn2 by 150-fold in wild-type mice at 24 h. Relative to wild-type littermates, Lcn2KO mice were markedly more sensitive to endotoxemia, exhibiting elevated indices of organ damage (transaminasemia, lactate dehydrogenase) and increased mortality. Such exacerbated endotoxemia was associated with substantially increased caspase-3 cleavage and concomitantly elevated immune cell apoptosis. Furthermore, cells from Lcn2KO mice were hyperresponsive to LPS ex vivo, exhibiting elevated cytokine secretion. Additionally, Lcn2KO mice exhibited delayed LPS-induced hypoferremia despite normal hepatic hepcidin expression and displayed decreased levels of the tissue redox state indicators cysteine and glutathione in liver and plasma. Desferroxamine, an iron chelator, significantly protects Lcn2KO mice from LPS-induced toxicity, including mortality, suggesting that Lcn2 may act as an antioxidant in vivo by regulating iron homeostasis. Thus, Lcn2-mediated regulation of labile iron protects the host against sepsis. Its small size and simple structure may make Lcn2 a deployable treatment for sepsis.
OriginalsprogEngelsk
TidsskriftJournal of Immunology
Vol/bind189
Udgave nummer4
Sider (fra-til)1911-9
Antal sider9
ISSN0022-1767
DOI
StatusUdgivet - 2012

ID: 36546512