In response to Toll-like receptor (TLR) triggering the innate immune system produces lipocalin-2, thus preventing bacteria from obtaining the iron that is essential to their growth and survival.
Bacterial survival and growth depends on iron, much of which is acquired from the host by siderophores that scavenge iron and transport it into the pathogen. However, as described in a recent Nature paper, the innate immune system of the host can prevent bacteria from obtaining iron by producing lipocalin-2, which sequesters bacterial siderophores, in response to Toll-like receptor (TLR) triggering.
In this report, Flo et al. show that stimulation of macrophages through TLRs induces marked upregulation of transcription of the lipocalin-2 gene. They confirm these results in vivo, showing that injection of mice with the TLR4 ligand lipopolysaccharide induces increased expression of lipocalin-2 in a TLR4-dependent manner. So, the authors generated lipocalin-2-deficient mice to assess the role of lipocalin-2 in bacterial infection. Although these mice remain healthy in specific-pathogen-free conditions, when challenged with Escherichia coli (strain H9049), they develop marked bacteraemia, have high bacterial loads in the blood, liver and spleen, and have accelerated morbidity at high doses, indicating that lipocalin-2 has an important role in innate defence against bacterial infection.
In the serum, the concentration of free iron is tightly regulated by iron-binding proteins such as transferrin, so invading pathogens must acquire iron by secreting siderophores, which effectively compete for iron. The authors have previously shown that lipocalin-2 can bind catecholate-type siderophores (such as enterochelin) but not other types of siderophore (such as ferrichrome). As E. coli strain H9049 depends on enterochelin for importing iron, its growth was inhibited when cultured in acute-phase serum from wild-type mice but not from lipocalin-2-deficient mice. By contrast, the in vitro growth of Staphylococcus aureus, which does not depend on enterochelin, was not affected by the presence of lipocalin-2.
The specificity of the protective effect of lipocalin-2 against enterochelin-dependent bacterial infection was then examined in vivo. Mice were challenged with E. coli either with or without co-injection of ferrichrome, which allows bacteria to acquire iron in an enterochelin-independent manner. Similar to lipocalin-2-deficient mice, wild-type mice that received bacteria and ferrichrome showed markedly increased morbidity, indicating that lipocalin-2 confers resistance to bacterial infection by abrogating enterochelin-dependent iron uptake by bacteria.
Lucy Bird
References
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestering iron. Nature432, 917–921 (2004) | Article | PubMed |
