Abstract
Lipocalins are a family of secreted adipokines which play important roles in various biological processes. Lipocalin-2 (LCN-2) has been shown to be involved in acute and chronic inflammation. This particular protein is critical in the pathogenesis of several diseases including cancer, diabetes, obesity, and multiple sclerosis. Herein, we discuss the general molecular basis for the involvement of LCN-2 in acute infections and chronic disease progression and also ascertain the probable role of LCN-2 in ocular diseases, particularly in age-related macular degeneration (AMD). We elaborate on the signaling cascades which trigger LCN-2 upregulation in AMD and suggest therapeutic strategies for targeting such pathways.
Electronic supplementary material
The online version of this article (10.1007/s00018-019-03423-8) contains supplementary material, which is available to authorized users.
Keywords: Lipocalin-2 (LCN-2), Age-related macular degeneration (AMD), Inflammation, AKT2 signaling, Retinal degeneration
Structure and expression of lipocalin-2 (LCN-2)
Lipocalin-2 (LCN-2) is a member of the broader lipocalin family of proteins that includes over 20 soluble proteins, most of which are extracellular [1–5]. This family is evolutionarily conserved and found in different lineages from bacteria to plants, invertebrates, and vertebrates (Fig. 1) [5]. Lipocalins have a three-dimensional structure (lipocalin domain) in which eight β-strands form a symmetrical β-barrel fold with a cylindrical shape (Fig. 2) [4]. The β-barrel structure provides a hydrophobic cavity to bind to a variety of lipophilic ligands [2], including retinoic acid, progesterone, prostaglandin, and fatty acids [6].
The lipocalin proteins play an important role in a variety of biological processes, including retinoid binding, immune responses, olfaction, pheromone transport, and prostaglandin synthesis [2, 7]. Additionally, lipocalins are associated with the regulation of critical cellular processes, such as proliferation, differentiation [8], migration [9], and survival [10]. Some lipocalins can be used as biomarkers of human diseases including tear lipocalin (TLC) [7], orosomucoid (α1-acid glycoprotein), protein HC (α1-microglobulin), apolipoprotein D, retinol-binding protein, complement C8, and prostaglandin D synthase [11].
In the human genome, the LCN-2 gene was found in a cluster of three lipocalins, on the long arm of chromosome 9 (syntenic to a region on mouse chromosome 4) [12]. Human LCN-2 protein was initially identified as a 25-kDa protein from phorbol myristate acetate (PMA) stimulated neutrophils that were bound to gelatinase [13–15]. Polyclonal antibodies raised against neutrophil gelatinase not only recognized gelatinase, but also this 25-kDa protein [14]. There are different names for human LCN-2 including neutrophil gelatinase-associated lipocalin (NGAL), human neutrophil lipocalin (HNL), uterocalin, 25 kDa α2-microglobulin-related protein, oncogene 24p3 protein (24p3), siderocalin, α2μ-globulin, neu-related lipocalin (NRL) in rat, and 24 kDa superinducible protein (Sip24) in mouse [16–19]. These names were chosen based either on the observed role of LCN-2 or the specific tissue in which its expression was first noticed [16]. There are two different forms of LCN-2, one form is monomeric with a 10-min half-life and the other is dimeric with a 20-min half-life [20].
Under normal physiological conditions, the LCN-2 mRNA is greatly expressed in bone marrow, but not in peripheral leukocytes (Fig. 3) [21]. Additionally, LCN-2 expression is induced during neutrophil development [12]. Higher levels of LCN-2 are found in tissues that are constantly exposed to microorganisms including prostate, salivary gland, uterus, stomach, colon, and appendix. Moreover, in some tissues such as kidney and liver, the level of LCN-2 is reduced during senescence [16, 22]. Although LCN-2 expression begins in the embryo [23], it has been demonstrated that it is strongly activated in inflamed organs, where it is expressed either by different resident cells or by circulating immune cells which enter the tissue [16, 24, 25]. A low level of LCN-2 is detectable in bodily fluids, however, under pathological conditions, this level may increase [16, 26].
In general, lipocalins bind to specific cell-surface receptors to transport ligands inside cells through receptor-mediated endocytosis [27]. Two different cell-surface receptors for LCN-2 have been described: solute carrier family 22 member 17 (SLC22A17, 24p3R or NGALR2) and low-density lipoprotein-related protein 2 (LPRP2 or megalin) [27–29]. High levels of 24p3R are regularly present in specific cells, including macrophages, neutrophils [30, 31], epithelia of respiratory and alimentary tracts [32], kidney epithelial cells [27], astrocytes [33], microglia [34], and neurons [35]. Megalin, a multi-ligand endocytic receptor, is highly expressed in some types of absorptive epithelial cells such as thyroid cells, epididymal, renal proximal tubule [36–42], and neuro-epithelium [43]. Sensory organs including eye (specifically the retinal ganglion cells) and ear also express megalin [44–49]. Additionally, it has been shown that in the optic nerve, megalin is selectively expressed by astrocytes during the development of oligodendrocyte precursor cells [50].
LCN-2 function in health and diseases
LCN-2 was first identified as a neutrophil granule component, with a strong binding affinity to bacterial catecholate-type ferric siderophores [51]. Iron is essential for bacterial growth and perpetuation, and lipocalin-2 confers its bactericidal affect against a number of bacterial species by chelating siderophore-bound iron and making it unavailable for bacterial utilization [51–53]. It has been linked as a definitive marker for several bacterial acute infections in humans [54]. LCN-2 is known to be highly elevated in patients with urinary tract [55, 56], Helicobacter pylori [57] and particularly Klebsiella pneumoniae infections [58], and it is thought to be a very useful marker to assess the severity and potential mortality of patients with community-acquired pneumonia [59]. The expression of the lcn2 gene has also been found to be upregulated in peripheral blood mononuclear cells (PBMCs) from severe acute respiratory syndrome (SARS) patients [60]. It is now known that human immunodeficiency virus (HIV) infection is associated with adipose tissue inflammation and LCN-2 activation [61]. Reduced LCN-2 levels are seen in nasopharyngeal aspirate samples from patients with severe influenza A(H1N1)pdm09 virus infection [62]. These results indicate that LCN-2 serves as an important marker for several infectious diseases, including HIV-related adipose tissue dysfunction and severe H1N1 infection [61, 62].
LCN-2 also plays an important role in immune activation during acute infection [53]. It is known to be expressed in macrophages and polymorphonuclear cells (PMNs) and to confer protection in an animal model of nephrotoxic serum nephritis induced by either acute kidney injury or bacterial infection by triggering apoptosis in the renal epithelial cells and limiting cytokine production by the TLR2 pathway [30]. In animal models of Salmonella typhimurium infection, LCN-2 confers host defense by regulating iron homeostasis and the inflammatory pathway in macrophages [63, 64]. In vivo models for mucosal infection due to Escherichia coli and Klebsiella pneumoniae exposure show increased expression of LCN-2 in an IL-22-dependent manner in intestinal epithelial cells, as part of the protective host-defense mechanism against such infection at mucosal surfaces [65]. In addition to the protective role of LCN-2 during acute infection, there is contrasting evidence which suggests otherwise. It has been shown that LCN-2 worsens pneumococcal pneumonia infection outcomes by deactivating alveolar macrophages in an animal model [66]. LCN-2 works as a source of iron to Mycobacterium tuberculosis in infected macrophages, facilitating mycobacterial growth in vivo [67]. LCN-2 also regulates iron homeostasis and exacerbates endotoxin-mediated sepsis [68], and regulates activation and tissue homing of innate immune cells, like neutrophils, during bacterial infection [69, 70]. LCN-2 also aggravates acute infectious colitis in mice by modulating PPARγ in intestinal epithelial cells [71].
Moreover, LCN-2 is known to be upregulated in several chronic diseases. Increased LCN-2 expression is seen in a variety of pathological states in the central nervous system, such as gliomas [72, 73], autoimmune disorders [74], brain injury [75, 76], and neurodegeneration [34, 77, 78]. Elevated expression of the protein was observed in mouse models of systemic lupus erythematosus, collagen-induced arthritis, and serum-transfer arthritis [79] and it has also been shown that deficiency of LCN-2 ameliorates experimental autoimmune encephalomyelitis in mice [80]. LCN-2 upregulation is linked to several human cancers with poor prognoses [81–83]. The elevated expression of the protein is also associated with obesity, insulin resistance, and hyperglycemia [84, 85], and with Crohn’s [86], chronic kidney [87], and liver [88] diseases. It has been also shown that the level of LCN-2 is significantly increased in the plasma and cerebrospinal fluids of patients with multiple sclerosis relative to healthy individuals, suggesting that LCN-2 may be an applicable biomarker for the disease [74].
These results indicate that LCN-2 plays a critical role in differential regulation of inflammation during acute infections and in the progression of several chronic diseases, thereby providing impetus for targeting this important adipokine for therapeutic interventions (Fig. 4). Moreover, our recent findings from a high-throughput protein–protein interaction array revealed that LCN-2 binds to several proteins responsible for regulating cell adhesion/migration, autophagy, inflammation, and post-translational modifications (Fig. 5). These findings suggest a multi-faceted role of this protein in regulating a number of cellular functions during normal and disease states.
Role of LCN-2 in ocular diseases: focus on age-related macular degeneration (AMD)
Consistent with its role in inflammation, apoptosis, and stress resistance during acute infections and in chronic diseases (as reviewed in section “LCN-2 function in health and diseases”), LCN-2 has recently been shown to be upregulated in a number of ocular pathologies. A few groups have reported that expression of LCN-2 was increased with the progression of experimental retinal degeneration induced in animal models by various factors and, most importantly, in the retinae of human AMD donors (Fig. 6) and in a mouse model (Fig. 7) with AMD-like pathology [89–92]. One of the easiest ways to induce retinal degeneration is to expose dark-adapted animals to high-intensity fluorescent light right after chemical pupil dilation [89, 93]. Both the LCN-2 mRNA and protein levels were significantly increased in the whole retinae of the rats after such induction of retinal degeneration, compared to the controls. Moreover, this increase coincided with the increased expression of Bim and caspase-3—markers of apoptosis. Importantly, knockdown or overexpression of LCN-2 in the retina (by intravitreal injections of either LV-shLCN-2 or LV-LCN-2) resulted in the corresponding changes in the expression of apoptotic markers, suggesting that LCN-2 is an upstream regulator of apoptosis in the light-induced model of retinal degeneration [93].
Another group used ATP-binding cassette subfamily A member 4 (Abca4)−/− retinol dehydrogenase 8 (Rdh8)−/− double-knockout mice to study retinal degeneration caused by the disruption of the visual cycle [94]. These mice exhibit several features of Stargardt disease (a form of hereditary macular degeneration that affects youths) as well as AMD. Exposure of Abca4−/−Rdh8−/− mice (an animal model for Stargardt disease and AMD) to high-intensity light exacerbated retinal damage allowing for studying the role of the acute stress response in retinal degeneration. Strikingly, LCN-2 mRNA expression was 22-fold higher in the eyes of Abca4−/−Rdh8−/− mice that were exposed to high-intensity light compared to those kept under normal lighting conditions. The retinal pigment epithelium (RPE) and the retina were identified to be the source of the elevated LCN-2 [89]. Importantly, the expression of the LCN-2 receptor 24p3r was increased in the RPE after exposure of Abca4−/−Rdh8−/− mice to intense light, suggesting the possible involvement of a receptor-mediated effect during the development of retina degeneration [94]. To examine the exact role of LCN-2 in retinal degeneration, LCN-2−/−Abca4−/−Rdh8−/− triple-KO mice were generated in a follow-up study [94]. As expected, the light-induced retinal damage was exaggerated by the introduction of the third LCN-2−/−Abca4−/−Rdh8−/− KO compared to the double Abca4−/−Rdh8−/− KO, with significant upregulated expression of pro-inflammatory genes and activation of microglia [94]. The in vivo studies were complemented by in vitro data using hiPS-RPE cells that demonstrated the antiapoptotic and indirect antioxidant (through overexpression of heme oxygenase 1 and superoxide dismutase 2) effects of LCN-2. Taken together, it can be concluded that LCN-2 plays a protective role in retinal degeneration caused by the disruption of the visual cycle [94].
Our lab has also reported increased levels of LCN-2 during the progression of AMD and focused on the upstream regulation of LCN-2 using the Cryba1 KO mouse model that exhibits a strong AMD-like phenotype caused by defective lysosomal clearance in the RPE cells (Fig. 6) [91, 92]. We have provided novel evidence that during chronic inflammation and the onset of the disease state, expression of LCN-2 in the retina is regulated not only by NF-κB, but also by STAT1, and that they may act together as an indispensable promoter-binding complex for stimulating lcn-2 gene expression in LPS-treated Cryba1 KO mice (Fig. 6) [92]. Furthermore, a human proteome high-throughput microarray assay revealed a novel interaction between βA3/A1-crystallin (protein encoded by Cryba1) and AKT2 (Fig. 8) [95], which, in turn, is associated with βB2-crystallin when phosphorylated. βB2 crystallin is also the strongest binding partner for βA3/A1-crystallin (Fig. 8), and this association may regulate phosphorylation of AKT2 in the inflamed retina [92]. Finally, AKT2 regulates phosphorylation of IKKα, which is required for activation of NF-κB, which, in turn, regulates expression of LCN-2 in the retina both in the mouse model and in AMD patients [92]. Overall, our study revealed a novel AKT2-NF-κB-LCN-2 signaling axis that may be a potential therapeutic target for AMD (Fig. 9) [92]. We have also shown that LCN-2 positive neutrophils infiltrate the retina of AMD patients, but not in the retinas of control subjects (Fig. 6) [92], indicating a possible role of these cells in AMD pathogenesis. Our recent publication also suggests that LCN-2 upregulation in neutrophils during inflammation drives its activation and tissue homing (Figs. 10, 11; Movie 1), thereby potentiating degenerative changes in the retina (Fig. 12), similar to changes observed in atrophic or dry AMD [96]. Interestingly, loss of LCN-2 in these neutrophils (neutrophils obtained from LCN-2 knockout mice) did not trigger retinal infiltration or degenerative changes even in the presence of inflammatory stimuli (Figs. 10–12). Taken together, these results indicate that LCN-2 is important for regulating neutrophils activation, retinal infiltration, and concomitant degenerative changes in the retina during AMD pathogenesis [96].
Recently, Parmar et al. suggested the existence of a negative feedback loop between LCN-2 and NF-κB, based on the finding that pre-treatment of hiPS-RPE with LCN-2 led to a decrease in the nuclear translocation of NF-κB p65 (a well-characterized hallmark of NF-κB activation) [94]. In agreement with Parmar’s in vitro data, LCN-2-mediated regulation of NF-κB activation has also been documented in inflammation during progression of endotoxin-induced uveitis, a well-established model of acute ocular inflammation. LCN-2 was significantly upregulated in the retinae of the rats after induction of uveitis, and played a protective anti-inflammatory role by negative regulation of phosphorylation and nuclear translocation of NF-κB p65 in Muller cells and retinal tissues [90]. An earlier study conducted using eyes from horses suffering from autoimmune equine recurrent uveitis also reported upregulation of LCN-2 expression compared to healthy eyes. However, in contrast to endotoxin-induced uveitis, where LCN-2 was mostly localized to the outer nuclear layer of the retina, in autoimmune uveitis, LCN-2 was present throughout the whole retina [89, 97]. Interestingly, infiltrating cells were found to express both LCN-2 and matrix metalloproteinase 9 (MMP-9), indicating the possibility of MMP-9 stabilization by LCN-2 [97]. Notably, LCN-2 was also found to be overexpressed and co-localized with MMP-9 in another ocular pathology, pterygium—a wing-shaped, epithelial-covered fibrovascular growth on the cornea, frequently characterized by inflammation and neovascularization [98]. Possible stabilization of MMP-9 by LCN-2 in pterygium could lead to dissolution of Bowman’s layer and invasion of the retina by limbal basal epithelial cells [97]. Even though no studies have directly linked overexpression of LCN-2 with neovascularization in pterygium, this link has been proposed in the mouse model for corneal neovascularization. The authors speculate that the increased expression of LCN-2 after induction of neovascularization with alkali burns could induce VEGF through regulation of HIF-1α [99]. Stabilization of MMP-9 by LCN-2 could also facilitate VEGF liberation thus promoting angiogenesis [99]. Interestingly, the interaction between LCN-2 and MMP-9 could also contribute to the TGF β-mediated epithelial-to-mesenchymal transition of the lens epithelial cells following cataract surgery [100, 101].
While the majority of studies on the role of LCN-2 in ocular health focus on intraocular inflammation, a few studies demonstrated that LCN-2 is involved in a number of optic nerve disorders. For example, LCN-2 expression was increased > 80 fold in the ganglion cells following optic nerve crush—a popular model for glaucoma and neuronal apoptosis due to axonal degeneration [102]. LCN-2 was also found to regulate inflammation in the optic nerve during the progression of optic neuritis [103]. Optic neuritis is frequently the first clinical manifestation of multiple sclerosis, and is characterized by acute self-limiting inflammation of the optic nerve associated with demyelination of the retinal ganglion cell axons and decreased visual acuity. Similar to intraocular inflammation, LCN-2 expression was found to be increased in the experimental autoimmune optic neuritis model; however, in this study, LCN-2 contributed to creation of a pro-inflammatory rather than an anti-inflammatory environment: KO of LCN-2 positively impacted the clinical prognosis. Demyelination, immune cell infiltration, activation of microglia, and astrocytes, as well as the production of cytokines and chemokines, were significantly reduced in the LCN-2 KO mice compared to controls. LCN-2 immunostaining co-localized with the astrocyte-specific marker glial fibrillary acidic protein (GFAP), suggesting that reactive astrocytes are the main sources of LCN-2 in the inflamed optic nerves. The authors speculate that the lack of the classical blood–brain-barrier properties of the optic nerve (compared to the retina) may facilitate the recruitment of immune cells and development of inflammation [103].
Overall, LCN-2 is significantly overexpressed not only in AMD, but in a variety of ocular pathologies, involving different tissues, which makes it an attractive therapeutic target for future drug development.
Targeting LCN-2 for therapeutic intervention in AMD: future prospects
AMD is the leading cause of blindness in the elderly population and is classified as either early/dry or wet AMD. About 90% of patients with AMD have the dry form of the disease, for which there is no effective treatment available at the present time [104]. Therefore, understanding the molecular pathways involving AMD pathogenesis and establishing a treatment for dry AMD is of paramount importance.
Targeting LCN-2 has been previously employed for treating diseases other than AMD. Specifically, LCN-2 inhibition has been used as a therapy for metastatic cancers [81, 105]. However, LCN-2 is not currently used for treatment of dry AMD. We have recently shown that LCN-2 expression was elevated in AMD retinae through activation of the AKT2-dependent pathway and that inhibiting AKT2 specifically could decrease LCN-2 levels in the retina (Fig. 13) [92]. We have recently shown that specifically blocking AKT2 (using AKT2 inhibitor CCT128930) in RPE cells could successfully mitigate inflammation (Fig. 14), neutrophil infiltration into the retina, Müller cell activation, and assauge dry AMD-like phenotype (Fig. 15) in the Cryba1 cKO mice [96]. Therefore, inhibiting AKT2 will also likely contribute to alterations in other intracellular pathways because of its involvement in many diverse signaling cascades [106]. Our previous study has proved that STAT1 is essential in lcn2 gene activation, particularly during the acute to chronic inflammatory transition in AMD [92]. Taken together, we hypothesize that inhibiting specific signaling molecules like interferons (IFNs), which activate STAT1 [107, 108], particularly during AMD pathogenesis, could be beneficial in ameliorating LCN-2 activation. Moreover, targeting LCN-2 with specific neutralizing antibodies or by gene silencing could also be beneficial in establishing a therapeutic regime for delaying the progression of dry AMD.
In this review, we have discussed the importance of LCN-2 in ocular diseases, mainly in AMD, and identified molecular cascades involved in the activation of the protein, which could be targeted for therapeutic interventions in the future.
Electronic supplementary material
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Acknowledgements
This study was funded by National Eye Institute: EY019037-S (DS), RPB/IRRF Catalyst Award for Innovative Research Approaches for AMD (DS), BrightFocus Foundation, Jennifer Salvitti Davis Chair in Ophthalmology (DS), Research to Prevent Blindness (Ophthalmology, UPMC), NY
Footnotes
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Contributor Information
Sayan Ghosh, Email: sayang@pitt.edu.
Debasish Sinha, Email: Debasish@pitt.edu.
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