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

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Abstract

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.

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Abbreviations

Lcn2:

Lipocalin 2

Lcn2KO:

Lipocalin 2 knockout

WT:

Wild-type

NGAL:

Neutrophil gelatinase-associated lipocalin

TG:

Triglycerides

LDH:

Lactate dehydrogenase

ALT:

Alanine transaminase

AST:

Aspartate transaminase

CI:

Catalytic iron

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Acknowledgments

We thank Dr. Gregory Shearer for his critical input.

Funding

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).

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Authors and Affiliations

  1. Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, 16802, USA

    Xia Xiao, Beng San Yeoh, Piu Saha, Rodrigo Aguilera Olvera, Vishal Singh & Matam Vijay-Kumar

  2. Department of Medicine, The Pennsylvania State University Medical Center, Hershey, PA, 17033, USA

    Matam Vijay-Kumar

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  1. Xia Xiao
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  2. Beng San Yeoh
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  3. Piu Saha
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Correspondence to Matam Vijay-Kumar.

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Xiao, X., Yeoh, B.S., Saha, P. et al. Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation. Biometals 29, 451–465 (2016). https://doi.org/10.1007/s10534-016-9925-5

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