Sphingosine 1-phosphate in disease: a focus on endometriosis, intrauterine fetal demise and sepsis

Sphingosine 1-phosphate (S1P) is a pleiotropic bioactive sphingolipid whose intracellular levels are tightly regulated by a balance of its synthesis, catalyzed by two isoforms of sphingosine kinase (SK1 and SK2), and its dephosphorylation brought about by S1P phosphatases (SPP1 and SPP2) or degradation by S1P lyase (SPL). S1P is known to modulate many physiological and pathological processes including inflammation, cell survival, proliferation and migration acting through a family of 5 G protein-coupled receptors (S1P1-5). In this work, we investigated the role of S1P in different pathological conditions, namely endometriosis, intrauterine fetal demise and sepsis. Endometriosis is a gynecological chronic inflammatory disease defined as the presence of endometrial glands and stroma outside the uterine cavity, that affects about 10% of reproductive-age women and has a major impact on the quality of life of the patients, as it is associated with chronic pelvic pain and infertility. Despite being very common, it is a challenging disease, due to a lack of specific treatments and an incomplete understanding of the molecular mechanisms involved in the pathogenesis. In the recent years, S1P signaling has been found to be deeply dysregulated in endometriosis. In this work, we investigated the molecular mechanisms involved in S1P signaling in the endometrium using cultured human endometrial stromal cells (HESC). We showed that S1P acts as a pro-inflammatory cue in HESCs, increasing the production of reactive oxygen species (ROS) and the expression of pro-inflammatory cytokines, through the activation of the mitogen-activated protein kinase ERK5 mediated by S1P1/3 signaling. Intrauterine fetal demise (IUFD), defined as a baby born dead at 28 weeks of gestation or more, or with a birthweight of ≥1000 g, or a body length of ≥35 cm, is a prominent issue worldwide, but because of the variety of classification systems and possible causes, a majority of cases is still reported as “unexplained”. Here, we investigated possible placental causes related to IUFD, by analyzing the placenta of 10 cases of IUFD compared to 10 controls. Pathological examination revealed the presence of a hypoxic-ischemic state, and the molecular analysis showed a dysregulation in the expression of various factors involved in fetal protection, inflammation, vascular growth, trophoblast migration and invasion, including receptors and enzymes involved in the S1P signaling pathway. Taken together, these data support an inflammatory state and a growth defect in the placenta, as well as a dysregulation of S1P signaling, that might be leading to IUFD. Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Various studies have shown an involvement of S1P in the condition, with a decrease of 4 serum and plasma S1P levels in sepsis patients. Interestingly, in the plasma of sepsis patients a redistribution of S1P from albumin (HSA) to HDL as its carrier was found, and a possible protective role in the disease for HDL-S1P specifically was suggested. In this study, we established a method to use a new technology, flow induced dispersion analysis (FIDA), to characterize the distribution of S1P among its carriers in plasma samples in a fast and easy way. We were able to confirm the shift from HSA-S1P to HDL-S1P in the patients compared to the controls; moreover, in the more severe cases, we found significant correlations between the levels of HDL-S1P measured with FIDA in plasma samples taken on day 1 after the diagnosis and important clinical outcomes several days later. Thus, this preliminary study shows promising results for the development of a fast and simple way of characterizing the distribution of S1P in patient plasma samples, that might also serve as a predictive factor for positive clinical outcome in the more severe cases. In conclusion, in the present work we explored aspects of S1P signaling in various prominent pathological conditions, with the aim of furthering our understanding of their pathogenesis and establishing the rationale for the exploitation of the S1P pathway for possible therapeutic or diagnostic approaches.