Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis
Document Type
Article
Publication Date
2012
Abstract
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. Copyright © 2012 by The American Association of Immunologists, Inc.
Publication Title
Journal of Immunology
Volume
189
Issue
4
First Page
1911
Last Page
1919
Recommended Citation
Srinivasan, Gayathri; Aitken, Jesse D.; Zhang, Benyue; Carvalho, Frederic A.; Chassaing, Benoit; Shashidharamurthy, Rangaiah; Borregaard, Niels; Jones, Dean P.; Gewirtz, Andrew T.; and Vijay-Kumar, Matam, "Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis" (2012). PCOM Scholarly Works. 556.
https://digitalcommons.pcom.edu/scholarly_papers/556
Comments
This article was published in Journal of Immunology, Volume 189, Issue 4, Pages 1911-1919.
The published version is available at http://dx.doi.org/10.4049/jimmunol.1200892.Copyright © 2012 Scopus.