Lipocalin 2 confers protection against endotoxin‐induced sepsis in mice

Abstract

Sepsis is characterized by elevated systemic proinflammatory cytokines and agents that can act as amplifiers (HMGB1) or dampeners (sIL‐1Ra) of inflammation and thus play a decisive role in sepsis. Lipocalin 2 (Lcn2), which is upregulated by log orders of magnitude during inflammation but its role in sepsis, is largely unknown. 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 and aminotransferases were analyzed. Splenocyte apoptosis was assayed 24h after LPS by TUNEL staining, caspase 3 and flow cytometry. Peritoneal cells from WT and Lcn2KO mice were stimulated with LPS and cytokines, COX2 and iNOS were analyzed. 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, splenocytes exhibited extensive apoptosis as measured by caspase 3 and TUNEL staining. Flow cytometry revealed that apoptosis of neutrophils, CD3+CD4+ and dendritic cells were significantly increased in Lcn2KO. Our data demonstrate that Lcn2 is a host protective factor during sepsis and, given its multifunctionality, small size, and simple structure it may be developed as potential therapeutic agent to treat sepsis.