The Neutrophil Lipocalin NGAL Is a Bacteriostatic Agent that Interferes with Siderophore-Mediated Iron Acquisition

Goetz, David H.; Holmes, Michael; Borregaard, Niels; Bluhm, Martin E.; Raymond, Kenneth N.; Strong, Roland K.

doi:10.1016/s1097-2765(02)00708-6

Cited by 1,214 publications

(1,290 citation statements)

References 57 publications

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“…Bacterial ferric siderophores are ligands for NGAL, and the ability of NGAL to sequester iron is important for its bacteriostatic effect in vivo (38)(39)(40). NGAL is also thought to mediate inflammatory responses by sequestering neutrophil chemoattractants, particularly N-formylated tripeptides, and possibly leukotriene B 4 , as well as platelet-activating factor (21).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Gupta¹,

Shukla²,

Cowland³

et al. 2007

Arthritis & Rheumatism

121

119

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Objective. Expression of matrix metalloproteinase 9 (MMP-9) is up-regulated in osteoarthritis (OA) and usually presents as multiple bands when synovial fluid (SF) from OA patients is analyzed by zymography. Among these bands is an ϳ125-130-kd band for high molecular weight (HMW) gelatinase, which has not been characterized. This study was undertaken to characterize the HMW MMP activity in OA SF.Methods. MMP activity in OA SF was determined by gelatin zymography. Recombinant MMPs were used to identify MMP activity on the zymogram. Western immunoblotting, immunoprecipitation, and immunodepletion analyses were performed using antibodies specific for human MMP-9 and human neutrophil gelatinase-associated lipocalin (NGAL). Human cartilage matrix degradation was determined by dimethylmethylene blue assay.Results. Zymographic analysis showed that the HMW gelatinase in OA SF comigrated with a purified NGAL-MMP-9 complex. Results of Western immunoblotting showed that the HMW gelatinase was also recognized by antibodies specific for human NGAL or human MMP-9. These same antibodies also immunoprecipitated the HMW gelatinase activity from OA SF. The NGAL-MMP-9 complex was reconstituted in vitro in gelatinase buffer. In the presence of NGAL, MMP-9 activity was stabilized; in the absence of NGAL, rapid loss of MMP-9 activity occurred. MMP-9-mediated release of cartilage matrix proteoglycans was significantly higher in the presence of NGAL (P < 0.05).Conclusion. Our findings demonstrate that the HMW gelatinase activity in OA SF represents a complex of NGAL and MMP-9. The ability of NGAL to protect MMP-9 activity is relevant to cartilage matrix degradation in OA and may represent an important mechanism by which NGAL may contribute to the loss of cartilage matrix proteins in OA.The developed world's aging population has experienced a dramatic increase in the incidence of joint dysfunction and osteoarthritis (OA), leading to a compromised quality of life. Aging, biomechanical stress, and oxidative stress, in addition to genetic factors and trauma, all appear to be associated with degenerative and progressive cartilage and bone changes in OA, particularly in the weight-bearing joints. Although OA is not considered an inflammatory disease by traditional standards, elevated levels of proinflammatory cytokines, such as interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣, have been observed in OA synovial fluid (SF), supporting the notion that there is an inflammatory component associated with the pathogenesis of OA (for review, see refs. 1-3).The only cell type present in articular cartilage is the chondrocyte, which is embedded within an extracellular matrix (ECM) primarily composed of type II collagen and aggrecan. Chondrocytes arise from a mesenchymal progenitor cell and are responsible for the biosynthesis of ECM proteins and their transport into the space occupied by the ECM. Chondrocytes play an important role in cartilage homeostasis by maintaining the proper balance between anabolic pathways, which Supported in part by the NIH...

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Section: Discussionmentioning

confidence: 99%

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Gupta¹,

Shukla²,

Cowland³

et al. 2007

Arthritis & Rheumatism

121

119

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“…Lcn2 plays a crucial role in antibacterial innate immune responses by virtue of its ability to bind iron siderophores 14, 15. In addition, its role in growth, differentiation and apoptosis of mammalian cells has been demonstrated and depends largely on regulation of iron homeostasis of the target cells 16, 17, 18, 19.…”

Section: Introductionmentioning

confidence: 99%

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

Ashraf

Schwelberger

Brendel

et al. 2016

American Journal of Transplantation

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Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor–recipient combinations (C57Bl/6 wild‐type and Lcn2−/−, Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation.

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“…Homologous proteins were also identified in the mouse (Lcn2/24p3/uterocalin) and rat (α 2 -microglobulin-related protein/neurelated lipocalin) [6]. Lcn2 can bind catecholate-type bacterial ferric siderophores [7] (e.g. enterobactin), which are low molecular compounds that bind ferric iron and are able to acquire iron from mammalian iron-binding proteins, including Tf and lactoferrin [8].…”

Section: Introductionmentioning

confidence: 99%

“…enterobactin), which are low molecular compounds that bind ferric iron and are able to acquire iron from mammalian iron-binding proteins, including Tf and lactoferrin [8]. Since Lcn2 binds enterobactin with higher affinity than the E. coli enterobactin transporter, it effectively interferes with bacterial iron uptake and, in fact, acts as a bacteriostatic agent [7].…”

Section: Introductionmentioning

confidence: 99%

Anemia upregulates lipocalin 2 in the liver and serum

Jiang

Constante

Santos

2008

Blood Cells, Molecules, and Diseases

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Lipocalin 2 (Lcn2), a mammalian protein that is expressed and secreted in various pathologic states, binds siderophores, which are high-affnity iron chelators. Besides its role in limiting iron availability to pathogens in the setting of bacterial infection, Lcn2:siderophore complexes can also deliver iron to cells. In this study, we examined Lcn2 regulation in the liver of mice in situations of increased iron utilization, namely, during anemia. Anemia induced by phlebotomy, iron deprivation, or phenylhydrazine treatment was associated with upregulation of Lcn2 gene expression in the liver and elevation of serum Lcn2 protein levels. We further explored the participation of several factors known to co-occur during anemia, including hypoxia, changes in iron levels, and erythropoietic drive, in the regulation of Lcn2 by anemia. We found that hypoxia, but not iron or erythropoietin, caused an induction of Lcn2 expression. The upregulation of Lcn2 levels by anemia and hypoxia, which is not directly mediated by iron or erythropoietin, suggests a possible physiological role for Lcn2 during increased iron utilization and mobilization from stores.

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The Neutrophil Lipocalin NGAL Is a Bacteriostatic Agent that Interferes with Siderophore-Mediated Iron Acquisition

Cited by 1,214 publications

References 57 publications

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

Anemia upregulates lipocalin 2 in the liver and serum

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