Teleologically, NGAL comprises a critical component of innate immunity to bacterial infection. Siderophores are synthesized by bacteria to scavenge iron from the surroundings, and use specific transporters to recover the siderophore–iron complex, ensuring their iron supply. The siderophore-chelating property of NGAL therefore renders it a bacteriostatic agent [25
]. Experimental evidence for this role is derived from mice that are genetically modified to lack the NGAL
gene, which renders them more susceptible to Gram-negative bacterial infections and death from sepsis [28
On the other hand, siderophores produced by eukaryotes participate in NGAL-mediated iron shuttling, which is critical to various cellular responses, such as proliferation and differentiation [26
]. This property provides a potential molecular mechanism for the documented role of NGAL in enhancing the epithelial phenotype. During kidney development, NGAL promotes epithelial differentiation of the mesenchymal progenitors, leading to the generation of glomeruli, proximal tubules, Henle’s loop and distal tubules [29
]. However, NGAL expression is also markedly induced in injured epithelial cells, including the kidney, colon, liver and lung. This is likely mediated via NF-κB, which is known to be rapidly activated in epithelial cells after acute injuries [31
], and plays a central role in controlling cell survival and proliferation [32
]. In the context of an injured mature organ, such as the kidney, the biological role of NGAL induction is one of marked preservation of function, attenuation of apoptosis and an enhanced proliferative response [33
]. This protective effect is dependent on the chelation of toxic iron from extracellular environments, and the regulated delivery of siderophore and iron to intracellular sites.
Finally, NGAL is markedly induced in a number of human cancers, where it often represents a predictor of poor prognosis [34
]. The NGAL
gene is known to be induced by a number of tumor-promoting agents, including SV40 and polyoma virus, phorbol esters, the transforming factor neu, hepatocyte growth factor, retinoic acid, glucocorticoids and NF-κB [35
]. The overexpressed NGAL protein binds to matrix metalloproteinase (MMP)-9, thereby preventing MMP-9 degradation and increasing MMP-9 enzyme activity. In turn, MMP-9 activity promotes cancer progression by degrading the basement membranes and extracellular matrix, liberating VEGF, and thus enabling angiogenesis, invasion and metastasis. Paradoxically, recent studies in some tumor cell lines have demonstrated that NGAL enhanced the epithelial phenotype, reduced tumor growth and suppressed metastasis – this prosurvival activity of NGAL is mediated by its ability to bind and transport iron inside the cells [34
A potentially unifying hypothesis to reconcile these seemingly contradictory roles of NGAL in human biology is offered in . Efficient mechanisms have evolved for the intracellular uptake of NGAL via receptors such as megalin, and for intracellular trafficking via endosomes. The subsequent molecular path taken by NGAL may be largely dependent on the type of molecule it is complexed with. NGAL that is devoid of siderophore and iron (holo-NGAL) rapidly scavenges intracellular iron. The resultant intra-cellular iron depletion results in a decrease in the mammalian cell’s proliferative ability and induction of apoptosis. On the other hand, when NGAL is bound to siderophore and iron, there is a rapid release of iron with regulation of iron-dependent molecular pathways, and downstream induction of proliferation and epithelial transformation. Finally, when NGAL is complexed with MMP-9 instead, there is enhancement of the active MMP-9 pool with resultant upregulation of MMP-9’s well known proangiogenic and proinvasive properties. Future studies aimed at further testing these hypotheses hold promise for advancing our understanding of NGAL biology.
The cellular role of neutrophil gelatinase-associated lipocalin may be dependent on the type of molecule it is complexed with