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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1911-1919
Number of pages9
JournalJournal of Immunology
Volume189
Issue number4
DOIs
StatePublished - Aug 15 2012

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Endotoxins
Sepsis
Homeostasis
Iron
Endotoxemia
Hepcidins
Deferoxamine
Mortality
Liver
Chelating Agents
Lipocalin-2
L-Lactate Dehydrogenase
Caspase 3
Oxidation-Reduction
Glutathione
Cysteine
Oxidative Stress
Antioxidants
Apoptosis
Cytokines

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Srinivasan, G., Aitken, J. D., Zhang, B., Carvalho, F. A., Chassaing, B., Shashidharamurthy, R., ... Kumar, M. V. (2012). Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis. Journal of Immunology, 189(4), 1911-1919. https://doi.org/10.4049/jimmunol.1200892
Srinivasan, Gayathri ; Aitken, Jesse D. ; Zhang, Benyue ; Carvalho, Frederic A. ; Chassaing, Benoit ; Shashidharamurthy, Rangaiah ; Borregaard, Niels ; Jones, Dean P. ; Gewirtz, Andrew T. ; Kumar, Matam Vijay. / Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis. In: Journal of Immunology. 2012 ; Vol. 189, No. 4. pp. 1911-1919.
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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.",
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Srinivasan, G, Aitken, JD, Zhang, B, Carvalho, FA, Chassaing, B, Shashidharamurthy, R, Borregaard, N, Jones, DP, Gewirtz, AT & Kumar, MV 2012, 'Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis', Journal of Immunology, vol. 189, no. 4, pp. 1911-1919. https://doi.org/10.4049/jimmunol.1200892

Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis. / Srinivasan, Gayathri; Aitken, Jesse D.; Zhang, Benyue; Carvalho, Frederic A.; Chassaing, Benoit; Shashidharamurthy, Rangaiah; Borregaard, Niels; Jones, Dean P.; Gewirtz, Andrew T.; Kumar, Matam Vijay.

In: Journal of Immunology, Vol. 189, No. 4, 15.08.2012, p. 1911-1919.

Research output: Contribution to journalArticle

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T1 - Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis

AU - Srinivasan, Gayathri

AU - Aitken, Jesse D.

AU - Zhang, Benyue

AU - Carvalho, Frederic A.

AU - Chassaing, Benoit

AU - Shashidharamurthy, Rangaiah

AU - Borregaard, Niels

AU - Jones, Dean P.

AU - Gewirtz, Andrew T.

AU - Kumar, Matam Vijay

PY - 2012/8/15

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N2 - 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.

AB - 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.

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Srinivasan G, Aitken JD, Zhang B, Carvalho FA, Chassaing B, Shashidharamurthy R et al. Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis. Journal of Immunology. 2012 Aug 15;189(4):1911-1919. https://doi.org/10.4049/jimmunol.1200892