, Volume 29, Issue 3, pp 451–465 | Cite as

Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation

  • Xia Xiao
  • Beng San Yeoh
  • Piu Saha
  • Rodrigo Aguilera Olvera
  • Vishal Singh
  • Matam Vijay-KumarEmail author


Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2, aka siderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicates the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participates in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects.


Lipocalin 2 Iron Catalytic iron Inflammation Anemia of inflammation Oxidative stress 



Lipocalin 2


Lipocalin 2 knockout




Neutrophil gelatinase-associated lipocalin




Lactate dehydrogenase


Alanine transaminase


Aspartate transaminase


Catalytic iron



We thank Dr. Gregory Shearer for his critical input.


This work was supported by grants from the National Institutes of Health (NIH) R01 (DK097865) and PSU Dean’s Schultz endowment, College of Health and Human Development Seed grant to M.V.-K. B.S.Y. is supported by NIH T32 (T32AI074551).

Compliance with ethical standards

Conflict of Interest

The authors have declared that no conflict of interest exists.

Supplementary material

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Supplementary material 1 (TIFF 594 kb)
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Supplementary material 2 (TIFF 1126 kb)
10534_2016_9925_MOESM3_ESM.docx (12 kb)
Supplementary material 3 (DOCX 11 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Xia Xiao
    • 1
  • Beng San Yeoh
    • 1
  • Piu Saha
    • 1
  • Rodrigo Aguilera Olvera
    • 1
  • Vishal Singh
    • 1
  • Matam Vijay-Kumar
    • 1
    • 2
    Email author
  1. 1.Department of Nutritional SciencesThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.Department of MedicineThe Pennsylvania State University Medical CenterHersheyUSA

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