Lipocalin 2 mediated hypoferremia protects against endotoxin- induced sepsis in mice (112.11)

Abstract

Abstract Sepsis is characterized by hypoferremia, a primitive protective mechanism to limit iron-induced oxidative stress. Lipocalin-2 (Lcn2) which is highly upregulated during inflammation and has been shown to transport iron under physiologic conditions. Accordingly, we hypothesized that such upregulation of Lcn2 serves to protect against sepsis associated oxidative stress. Lcn2 deficient mice (Lcn2KO) and their WT littermates were given E. coli LPS (20mg/kg BW) i.p. and monitored for mortality. Serum TNFα, IL-18, LDH, aminotransferases, iron, glutathione and cysteine were analyzed. Splenocyte apoptosis was assayed by TUNEL, caspase 3 cleavage and flow cytometry. In WT mice, LPS-induced systemic Lcn2 peaked at 24h and returned to basal levels by 48h. All Lcn2KO died by day 8 while only 20% mortality was observed in WT mice. In addition, Lcn2KO exhibited substantial elevation of every parameter tested including both pro- and anti-inflammatory cytokines. Further,Lcn2KO splenocytes exhibited extensive apoptosis as measured by caspase 3 cleavage, TUNEL staining and flow cytometry. More importantly, when compared to WT mice, Lcn2KO mice failed to exhibit LPS-induced hypoferremia at early time points and exhibited severe hepatic oxidative stress. Our data demonstrate that Lcn2 facilitates LPS-induced hypoferremia and serves as a host protective factor by reducing oxidative stress. Given Lcn2 multifunctionality, it may be developed as a potential therapeutic agent to treat sepsis.