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Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron

Nature volume 432, pages 917–921 (2004)Cite this article

Abstract

Although iron is required to sustain life, its free concentration and metabolism have to be tightly regulated1. This is achieved through a variety of iron-binding proteins including transferrin and ferritin2. During infection, bacteria acquire much of their iron from the host by synthesizing siderophores that scavenge iron and transport it into the pathogen3,4. We recently demonstrated that enterochelin, a bacterial catecholate siderophore, binds to the host protein lipocalin 2 (ref. 5). Here, we show that this event is pivotal in the innate immune response to bacterial infection. Upon encountering invading bacteria the Toll-like receptors on immune cells stimulate the transcription, translation and secretion of lipocalin 2; secreted lipocalin 2 then limits bacterial growth by sequestrating the iron-laden siderophore. Our finding represents a new component of the innate immune system and the acute phase response to infection.

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Figure 1: Lipocalin 2 production is induced through TLRs.
Figure 2: Lipocalin 2 protects against infection with E. coli.
Figure 3: Lipocalin 2 specifically inhibits enterochelin-dependent growth of E. coli.
Figure 4: Lipocalin 2 protection against bacterial infection is siderophore specific.

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Acknowledgements

We acknowledge T. Hawn and M. Matsumoto for discussions. This work was supported by grants from The Norwegian Research Council (to T.H.F.) and the NIH (to A.A., R.K.S. and K.D.S.).

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Author notes

  1. Trude H. Flo and Kelly D. Smith: These authors contributed equally to this work

Authors and Affiliations

  1. Institute for Systems Biology, 98103, Seattle, Washington, USA

    Trude H. Flo, Kelly D. Smith, David J. Rodriguez & Alan Aderem

  2. Institute for Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7489, Trondheim, Norway

    Trude H. Flo

  3. Department of Pathology, University of Washington, 98195, Seattle, Washington, USA

    Kelly D. Smith

  4. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Corporation, 565-0871, Osaka, Japan

    Shintaro Sato & Shizuo Akira

  5. Fred Hutchinson Cancer Research Center, 98109, Seattle, Washington, USA

    Margaret A. Holmes & Roland K. Strong

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Corresponding author

Correspondence to Alan Aderem.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Targeted disruption of the mouse Lcn2 gene. (JPG 36 kb)

Supplementary Figure 2

Liver inflammation, spleen iron and infiltrating neutrophils after i.p. infection of lipocalin 2 knockout (-/-) and wild type (+/+) mice with 0.6 ´ 108 c.f.u. E. coli H9049. (JPG 78 kb)

Supplementary Figure 3

Lipocalin 2 deficiency does not affect induction apoptosis upon withdrawal of IL-3 from IL-3-dependent bone marrow cells. (JPG 30 kb)

Supplementary Table 1

Blood and peritoneal cell populations in lipocalin 2-deficient and WT mice. (DOC 23 kb)

Supplementary Table 2

Serum iron and iron binding capacities in lipocalin 2 deficient and wild-type mice. (DOC 20 kb)

Supplementary Figure Legends

Legends to accompany Supplementary Information Figures 1–3. (DOC 22 kb)

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Flo, T., Smith, K., Sato, S. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004). https://doi.org/10.1038/nature03104

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