Neutrophil Gelatinase-associated Lipocalin, a Siderophore-binding Eukaryotic Protein

The Granulocyte Research Laboratory, Department of Hematology, University of Copenhagen, Rigshospitalet-4042, 9 Blegdamsvej, Copenhagen Ø, DK 2200, Denmark.
BioMetals (Impact Factor: 2.5). 05/2006; 19(2):211-5. DOI: 10.1007/s10534-005-3251-7
Source: PubMed


NGAL (neutrophil gelatinase-associated lipocalin) also known as lcn2 or siderochalin is constitutively expressed in myelocytes and stored in specific granules of neutrophils. It is highly induced in a variety of epithelial cells during inflammation. Analysis of the crystal structure of NGAL expressed in E.coli showed that NGAL has the ability to bind catecholate type siderophores and in this way prevent bacteria from acquisition of siderophore-bound iron. NGAL (or 24p3 as the highly homologous murine orthologue is named) knock out mice have a profound defect in defense against E.coli after intraperitoneal injection. This defect can be mimicked in wild-type mice by providing siderophore iron, which cannot be sequestered by NGAL, testifying to the specific role of NGAL as a siderophore binding protein in innate immunity. Megalin, a scavenger receptor functions as a receptor for NGAL and mediates uptake into endosomes, but other NGAL receptors are likely to exist.

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    • "Two receptors have been proposed: the solute carrier family 22 member 17 (SLC22A17 or 24p3R) that binds to mouse Lcn2 (Devireddy et al., 2005) and the megalin/ glycoprotein GP330, a low-density lipoprotein receptor that binds human LCN2 protein (Hvidberg et al., 2005). LCN2 is expressed in multiple tissues including uterus (Huang et al., 1999), immune cells (Borregaard & Cowland, 2006), liver, spleen, kidney in mice (Aigner et al., 2007), bone marrow, and in the tissues that are exposed to microorganisms (Cowland & Borregaard, 1997), and it has been recently identified in chondrocytes (Owen et al., 2008), although WAT is thought to be the main source (Yan et al., 2007). As outlined in the following subsections (Figure 1), LCN2 is involved in a series of processes such as apoptosis of hematopoietic cells (Devireddy et al., 2001), transport of fatty acids (Chu et al., 1998), and iron (Yang et al., 2002), modulation of inflammation (Cowland & Borregaard, 1997), and metabolic homeostasis (Yan et al., 2007). "
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    ABSTRACT: Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is a secreted glycoprotein that belongs to a group of transporters of small lipophilic molecules in circulation. LCN2 has been recently characterized as an adipose-derived cytokine. This adipokine is believed to bind small substances, such as steroids and lipopolysaccharides, and has been reported to have roles in the induction of apoptosis in hematopoietic cells, transport of fatty acids and iron, modulation of inflammation, and metabolic homeostasis. Recently, LCN2 has emerged as a useful biomarker and rheumatic diseases. This review provides an overview of LCN2 in inflammation, immunity, and metabolism.
    Full-text · Article · Dec 2015 · Biomarkers
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    • "Lipocalin-2, an acute phase protein that is a component of neutrophil granules, is involved in iron sequestration and is a biomarker for inflammation and sepsis (Bachman et al., 2009; Borregaard & Cowland, 2006; Li & Chan, 2011). Secretion of lipocalin-2 involves signalling via Toll-like receptor 4 (TLR4) and subsequent NF-kB binding to consensus sequences upstream of the lipocalin-2 promoter (Flo et al., 2004; Li & Chan, 2011), and its production is regulated via IL-1b, IL-17A and other cytokines (Chan et al., 2009; Kolls et al., 2008; Li & Chan, 2011). "
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    ABSTRACT: Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce interferon-gamma, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with wild type (WT) Cryptococcus. Considering that individuals with suppressed T CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether or not antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured the levels of antimicrobial peptides Lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors TLR4 and the receptor for advanced glycation end products [RAGE] in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of Lipocalin-2, S100A8, S100A9, and SAA3 as well as TLR4+ and RAGE+ macrophages and dendritic cells in mice inoculated with H99γ compared to WT H99. Similar results were observed in the lungs of H99γ-immunized, compared to heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22 deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared to WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.
    Full-text · Article · Apr 2014 · Microbiology
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    • "Lipocalin 2 (LCN2), also known as siderocalin, 24p3, uterocalin, and neutrophil gelatinase-associated lipocalin (NGAL), is a recently identified glycoprotein stored in neutrophil granules [120] but mainly produced by WAT [121, 122]. LCN2 has been isolated in different isoforms and its functions are carried out by the activation of the cellular receptor megalin [123]. "
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by severe joint injury. Recently, research has been focusing on the possible identification of predictor markers of disease onset and/or progression, of joint damage, and of therapeutic response. Recent findings have uncovered the role of white adipose tissue as a pleiotropic organ not only specialized in endocrine functions but also able to control multiple physiopathological processes, including inflammation. Adipokines are a family of soluble mediators secreted by white adipose tissue endowed with a wide spectrum of actions. This review will focus on the recent advances on the role of the adipokine network in the pathogenesis of RA. A particular attention will be devoted to the action of these proteins on RA effector cells, and on the possibility to use circulating levels of adipokines as potential biomarkers of disease activity and therapeutic response.
    Full-text · Article · Mar 2014 · Mediators of Inflammation
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