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


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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  1. Weinberg, E. D. Iron withholding: a defense against infection and neoplasia. Physiol. Rev. 64, 65–102 (1984)

    Article  CAS  Google Scholar 

  2. Andrews, N. C. Iron homeostasis: insights from genetics and animal models. Nature Rev. Genet. 1, 208–217 (2000)

    Article  CAS  Google Scholar 

  3. Ratledge, C. & Dover, L. G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000)

    Article  CAS  Google Scholar 

  4. Faraldo-Gomez, J. D. & Sansom, M. S. Acquisition of siderophores in gram-negative bacteria. Nature Rev. Mol. Cell Biol. 4, 105–116 (2003)

    Article  CAS  Google Scholar 

  5. Goetz, D. H. et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10, 1033–1043 (2002)

    Article  CAS  Google Scholar 

  6. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003)

    Article  CAS  Google Scholar 

  7. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002)

    Article  CAS  Google Scholar 

  8. Kjeldsen, L., Cowland, J. B. & Borregaard, N. Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Biochim. Biophys. Acta 1482, 272–283 (2000)

    Article  CAS  Google Scholar 

  9. Triebel, S., Blaser, J., Reinke, H. & Tschesche, H. A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinase. FEBS Lett. 314, 386–388 (1992)

    Article  CAS  Google Scholar 

  10. Kjeldsen, L., Johnsen, A. H., Sengelov, H. & Borregaard, N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J. Biol. Chem. 268, 10425–10432 (1993)

    CAS  PubMed  Google Scholar 

  11. Flower, D. R., North, A. C. & Attwood, T. K. Mouse oncogene protein 24p3 is a member of the lipocalin protein family. Biochem. Biophys. Res. Commun. 180, 69–74 (1991)

    Article  CAS  Google Scholar 

  12. Liu, Q., Ryon, J. & Nilsen-Hamilton, M. Uterocalin: a mouse acute phase protein expressed in the uterus around birth. Mol. Reprod. Dev. 46, 507–514 (1997)

    Article  CAS  Google Scholar 

  13. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998)

    Article  ADS  CAS  Google Scholar 

  14. Lien, E. et al. Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J. Biol. Chem. 274, 33419–33425 (1999)

    Article  CAS  Google Scholar 

  15. Ozinsky, A. et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc. Natl Acad. Sci. USA 97, 13766–13771 (2000)

    Article  ADS  CAS  Google Scholar 

  16. Takeuchi, O. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14 (2002)

    Article  CAS  Google Scholar 

  17. Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001)

    Article  ADS  CAS  Google Scholar 

  18. Xu, S. & Venge, P. Lipocalins as biochemical markers of disease. Biochim. Biophys. Acta 1482, 298–307 (2000)

    Article  CAS  Google Scholar 

  19. Liu, Q. & Nilsen-Hamilton, M. Identification of a new acute phase protein. J. Biol. Chem. 270, 22565–22570 (1995)

    Article  CAS  Google Scholar 

  20. Winkelmann, G. Microbial siderophore-mediated transport. Biochem. Soc. Trans. 30, 691–696 (2002)

    Article  CAS  Google Scholar 

  21. Yang, J. et al. An iron delivery pathway mediated by a lipocalin. Mol. Cell 10, 1045–1056 (2002)

    Article  CAS  Google Scholar 

  22. Suire, S., Stewart, F., Beauchamp, J. & Kennedy, M. W. Uterocalin, a lipocalin provisioning the preattachment equine conceptus: fatty acid and retinol binding properties, and structural characterization. Biochem. J. 356, 369–376 (2001)

    Article  CAS  Google Scholar 

  23. Devireddy, L. R., Teodoro, J. G., Richard, F. A. & Green, M. R. Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science 293, 829–834 (2001)

    Article  CAS  Google Scholar 

  24. Hou, Z., Stack, T. D. P., Sunderland, C. J. & Raymond, K. N. Enhanced iron (III) chelation through ligand predisposition: Syntheses, structures and stability of Tris-catecholate enterobactin analogs. Inorg. Chim. Acta 263, 341–355 (1997)

    Article  CAS  Google Scholar 

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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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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).

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