Abstract
Lipocalin 2 (Lcn2) is an essential component of the antimicrobial innate immune system. It attenuates bacterial growth by binding and sequestering the iron-scavenging siderophores to prevent bacterial iron acquisition. Whereas, the ability of Lcn2 to sequester iron is well-described, the role of Lcn2 in regulating immune cells during bacterial infection remains unclear. In this study, we showed that upon infection with Escherichia coli (O157:H7), Lcn2-deficient (Lcn2−/−) mice carried more bacteria in blood and liver, and the acute-phase sera lost their antibacterial activity in vitro. Neutrophils from Lcn2−/− mice were defective in homeostasis and morphological development. E. coli O157:H7 infection of Lcn2−/− mice resulted in a reduced neutrophil migration capacity, with 30% reduction of extravasated neutrophils, and impaired chemotaxis, as shown by a reduction in the secretion of chemoattractants, such as tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2, which are instrumental in eliciting a neutrophil response. We also found that some secreted cytokines [interleukin (IL)-6, IL-1β, and TNF-α] were decreased. Transcripts of inflammatory cytokines (IL-6, IL-1β, TNF-α, and IL-10), chemokines (MIP-2 and MCP-1), and iNOS production were all strongly repressed in Lcn2−/− macrophages. Furthermore, Lcn2 could induce the production of chemokines and promote the migration and phagocytosis of macrophages. Thus, Lcn2 deficiency could impair the migration and chemotaxis ability of neutrophils and disturb the normal secretion of inflammatory cytokines of macrophages. Therefore, the heightened sensitivity of Lcn2−/− mice to E. coli O157:H7 is not only due to the antibacterial function of Lcn2 but also a consequence of impaired functions of immune cells, including neutrophils and macrophages.
Highlights
Iron is an essential micronutrient required for almost all aerobic organisms, with crucial functions in many critical metabolic processes, such as DNA synthesis, oxygen transport, redox reaction, and synthesis of hemoglobin [1]
It seems that lipocalin 2 (Lcn2) expression is mainly induced in the liver during E. coli O157:H7 infection
In order to determine the direct bacteriostatic activity of Lcn2, sera from Lcn2−/− mice inoculated by heat-killed E. coli O157:H7 were collected 5 hpi and used for bacterial incubation
Summary
Iron is an essential micronutrient required for almost all aerobic organisms, with crucial functions in many critical metabolic processes, such as DNA synthesis, oxygen transport, redox reaction, and synthesis of hemoglobin [1]. Both hosts and pathogens depend on and compete for iron for their proliferation and biologic functions. In the struggle for iron, bacteria have evolved aggressive ironacquiring mechanisms through the expression of siderophores to steal iron from host proteins, such as transferrin and ferritin [3]. In order to restrict bacteria from obtaining iron, the hosts have adopted some “nutritional immunity” mechanisms for the competition of iron, including lipocalin 2 (Lcn2) [6]. Lcn has higher affinity to enterobactin-Fe3+ than enterobactin receptor protein FepA of E. coli, so it can inhibit the iron uptake pathway of E. coli and disrupt bacterial iron acquisition [7]
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