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

Trude H Flo; Kelly D Smith; Shintaro Sato; David J Rodriguez; Margaret A Holmes; Roland K Strong; Shizuo Akira; Alan Aderem

doi:10.1038/nature03104

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

Nature. 2004 Dec 16;432(7019):917-21. doi: 10.1038/nature03104. Epub 2004 Nov 7.

Authors

Trude H Flo¹, Kelly D Smith, Shintaro Sato, David J Rodriguez, Margaret A Holmes, Roland K Strong, Shizuo Akira, Alan Aderem

Affiliation

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

PMID: 15531878
DOI: 10.1038/nature03104

Abstract

Although iron is required to sustain life, its free concentration and metabolism have to be tightly regulated. This is achieved through a variety of iron-binding proteins including transferrin and ferritin. During infection, bacteria acquire much of their iron from the host by synthesizing siderophores that scavenge iron and transport it into the pathogen. 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Proteins / deficiency
Acute-Phase Proteins / genetics
Acute-Phase Proteins / metabolism*
Animals
Enterobactin / metabolism
Escherichia coli / growth & development
Escherichia coli / metabolism
Escherichia coli Infections / immunology*
Escherichia coli Infections / metabolism
Escherichia coli Infections / microbiology
Female
Immunity, Innate / immunology*
Iron / metabolism*
Lipocalin-2
Lipocalins
Male
Membrane Glycoproteins / deficiency
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mice
Mice, Inbred C57BL
Oncogene Proteins / deficiency
Oncogene Proteins / genetics
Oncogene Proteins / metabolism*
Protein Binding
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Cell Surface / deficiency
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism
Substrate Specificity
Toll-Like Receptors

Substances

Acute-Phase Proteins
Lipocalin-2
Lipocalins
Membrane Glycoproteins
Oncogene Proteins
RNA, Messenger
Receptors, Cell Surface
Toll-Like Receptors
Lcn2 protein, mouse
Enterobactin
Iron