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

    104 Citationer (Scopus)

    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.
    OriginalsprogEngelsk
    TidsskriftJournal of Immunology
    Vol/bind189
    Udgave nummer4
    Sider (fra-til)1911-9
    Antal sider9
    ISSN0022-1767
    DOI
    StatusUdgivet - 2012

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