Lipocalin 2 Bolsters Innate and Adaptive Immune Responses to Blood-Stage Malaria Infection by Reinforcing Host Iron Metabolism

Abstract

Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses.

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

“…Malaria infection results in a redistribution of host iron in order to limit iron availability to the invading parasite (15,19). It has been suggested that parasite growth is inhibited during IDA due to an additional reduction in the bioavailability of iron (46).…”

“…It has been speculated that an excess of iron bioavailability resulting from iron supplementation may subvert these processes and encourage parasite growth (16,17). Expression of the iron-regulatory protein lipocalin 2 (LCN2) is increased during malaria infection (18), and studies of knockout mice indicate a key role for LCN2 in modulating the innate and adaptive immune responses to infection through its influence on iron recycling (19). It is speculated that LCN2 redistributes iron to control erythropoiesis and immune cell development during infection, although it remains to be seen if this may be influenced by iron deficiency or supplementation.…”

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

“…Although it is beyond the scope of this review, iron is a critical target of innate immunity. The immune system attempts to sequester iron from colonizing microorganisms in order to suppress their proliferation by expressing ironbinding molecules (Correnti and Strong 2012;Zhao et al 2012). In rivalry with the host, the microorganisms acquire iron and/or heme by producing siderophores (Correnti and Strong 2012).…”

Lipocalin 2 binds to membrane phosphatidylethanolamine to induce lipid raft movement in a PKA-dependent manner and modulates sperm maturation

“…It is also well known as an innate immune factor that captures the siderophore, a molecular complex crucial for bacterial iron uptake, and suppresses bacterial growth (Goetz et al, 2002;Flo et al, 2004;Berger et al, 2006). More recently, LCN2 was shown to suppress bloodstream malarial growth by activating both innate and adaptive immune systems via an iron metabolism-reinforcing function (Zhao et al, 2012).…”