Overview of the expression patterns and roles of Lipocalin 2 in the reproductive system.

LCN2 is a known acute phase protein in non-reproductive tissues ( 52 ). Interestingly, a study examined Lcn2 in the context of uropathogenic infections ( 99 ). In murine cauda epididymis, Lcn2 mRNA was significantly increased after infection with uropathogenic E. coli , highlighting the antibacterial activity of LCN2 in reproductive tissues as seen in female uterine tissue ( 16 , 99 ). Male infertility can be caused by diseases of the testicles themselves or impaired testicular function, including defects in spermatogenesis, Leydig cell degeneration or poor sperm quality ( 100 ). One study from 2017, detected a strongly increased expression of Lcn2 expression in the testes in mice as a consequence of induced infertility by busulfan treatment or bilateral cryptorchidism ( 35 ). Although the study did not examine molecular signaling mechanisms, the authors speculated that LCN2 is involved in germ cell apoptosis. Tanaka and colleagues conducted a study on the involvement of spermatogonia in testicular gene regulation. They discovered that germ cell-deficient mice completely lose the expression of certain genes, including Lcn2 ( 32 ). Furthermore, they examined Lcn2 expression in a juvenile spermatogonial depleted ( jsd/jsd ) mouse mutant, which has severe defects in spermatogonial differentiation (seminiferous tubules containing only type A spermatogonial germ cells and Sertoli cells), and in an artificial cryptorchid model ( 32 ). Interestingly, both models exhibited high expression of Lcn2 in the testis, suggesting a potential relationship between Lcn2 and germ cell apoptosis ( 32 ). Kessel et al. analyzed LCN2 expression in testes from adult infertile Esr1 -deficient mice ( 31 ). Interestingly, LCN2 protein expression was strongly increased in these animals compared with age-matched WT animals ( 31 ). These studies provide evidence that LCN2 has not only a physiological but also a pathophysiological role in the testes. However, it is mandatory to understand the underlying molecular mechanism, which likely involves estrogen receptor signaling. Apart from its role in benign prostate diseases and the development and progression of prostate cancer ( 10 , 101 ), LCN2 has hardly been studied at all in diseases of the male reproductive tract. In 2005, a study analyzed adult male germ cell tumors and found a high increase in LCN2 in teratomas without seminomas but not in other subtypes, classifying it as an suitable predictor ( 102 ). For a more comprehensive understanding, it is also important to investigate the expression and localization of LCN2 in healthy human testes and in various diseases such as testicular cancer.

Lipocalin 2 (LCN2) is a member of the lipocalin family of proteins known for its specific lipocalin fold that forms a hydrophobic pocket, thus allowing them to act as transport proteins ( 1 ). LCN2 was first isolated from human neutrophils and reported as neutrophil gelatinase-associated protein (NGAL) that served as bacterial iron sequester ( 2 ). It is believed that its multiple functions probably stem from its ability to act as a monomeric protein (25 kDa), as a homodimer (~46 kDa), and as a heterodimer (~135 kDa) in a complex with matrix metalloproteinase 9 (MMP9) ( 3 ). Importantly, only human LCN2 can form dimers ( 4 ), whereas murine LCN2 lacks Cys 87 which is required for covalent disulfide bond formation ( 5 ). Due to its pleiotropic nature, LCN2 was rediscovered and given several names, some of which being oncogene 24p3, siderocalin, p25, α2-microglobulin-related protein and migration-stimulating factor inhibitor (MSFI) ( 6 – 8 ). The protein was given the name siderocalin because LCN2 has the ability to reduce bacterial growth, as it can bind iron indirectly via bacterial siderophores ( 6 , 9 ). In addition to its physiological role in host immune defense, aberrant expression of LCN2 has been observed under various pathophysiological conditions ( 10 – 12 ). A role of LCN2 in reproductive tissue was suspected early on after its discovery. Because LCN2 was found to be strongly expressed in the uterine tissue of mice, the term ‘uterocalin’ for LCN2 was introduced ( 13 ). However, there are relatively few historical studies in the area of LCN2 in the reproductive system. Even less data is available on the molecular mechanisms by which LCN2 mediates signal transduction in the healthy reproductive system. Currently, three different putative LCN2 receptors, namely soluble carrier family 22 member 17 (SLC22A17), megalin and melanocortin-4 receptor (MC4R), have been described and comprehensively reviewed in ( 14 ). The role of these receptors in the reproductive tract is still poorly understood. However, there is evidence that sex hormones influence the expression of LCN2 in mice and humans ( 15 – 17 ). With this review, our goal was to summarize the available knowledge on LCN2 in female and male reproductive organs. The focus was mainly on the female reproductive tract (uterus, vagina, and ovary). However, in the male reproductive tract, we concentrated on the expression of LCN2 in the testes and epididymis, as its expression in healthy and diseased prostates has been previously summarized ( 10 ).

The presence of LCN2 has been confirmed in both male and female healthy reproductive systems by multiple studies. However, the available studies show that LCN2 has so far been studied much more intensively in a pathological context than in a physiological context. Nevertheless, we can speculate about the different functions of LCN2 in the female and male reproductive tract. Although it appears that in the female reproductive system LCN2 is involved in tissue reorganization during the menstrual cycle and pregnancy, the mechanism of its action and the cells responsible for its production have not yet been determined. However, it has been shown to serve as a component of the maturation and motility component of sperm in male reproductive organs. Furthermore, several studies report the deregulation of LCN2 in numerous reproductive tissue pathologies, including fertility defects. Considering that the literature overview provides clear evidence that LCN2 is a key component in fertility, and that no information on the actual mechanisms of its action is currently available, further research on this topic would be beneficial to understand its precise function in the reproductive system, as well as its therapeutic potential.

MK: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. PBMS: Data curation, Visualization, Writing – review & editing. RW: Data curation, Funding acquisition, Supervision, Writing – review & editing. SKS: Conceptualization, Data curation, Supervision, Writing – original draft, Writing – review & editing.