Sphingosine 1-phosphate receptors are dysregulated in endometriosis: possible implication in transforming growth factor β–induced fibrosis

Bernacchioni, Caterina; Capezzuoli, Tommaso; Vannuzzi, Valentina; Malentacchi, Francesca; Castiglione, Francesca; Cencetti, Francesca; Ceccaroni, Marcello; Donati, Chiara; Bruni, Paola

doi:10.1016/j.fertnstert.2020.08.012

Cited by 25 publications

(37 citation statements)

References 54 publications

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“…We showed that S1P is produced via SphK in endometriotic lesions and is involved in the pathogenesis of endometriosis, inducing proliferation of endometriotic cells and induction of IL-6, an inflammatory agent [ 11 ]. Moreover, Bernacchioni et al recently reported the role of the S1P signaling axis in endometriosis-associated fibrosis [ 14 ]. S1P is also known to be abundantly contained in red blood cells and platelets [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

et al. 2021

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Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis.

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Section: Introductionmentioning

confidence: 99%

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

et al. 2021

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“…Fibrosis is one of the most common features of endometrial lesions, contributing to tissue adhesions, anatomic distortions, and scarring, and is an important cause of pelvic pain and infertility (Bernacchioni et al, 2021). A study comfirmed that the extent of lesional and cortical fibrosis are correlated with the severity of dysmenorrhea in women with ovarian EMs (Nie et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells

et al. 2022

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Endometriosis (EMs) is defined as the presence of tissue somewhat resembling endometrial glands and stroma outside the uterus; the retrograded endometrium grows in the peritoneal cavity and elicits fibrosis. Ferroptosis is a recently discovered form of programmed cell death, which is iron-dependent. The induction of ferroptosis has been found to participate in fibrosis. However, the relationship between EMs fibrosis and ferroptosis remains unknown. In this study, we confirmed that the iron content in ectopic stromal tissue in ovarian EMs is significantly increased. We explored the role of iron-induced ferroptosis in the pathogenesis of ovarian EMs fibrosis for the first time. We found that ferroptosis in ectopic tissues was significantly enhanced than that in eutopic tissues. Furthermore, we performed in vivo drug screening and found that ferroptosis induced by ferric ammonium citrate (FAC) could aggravate fibrosis. To clarify the mechanism of this process, the stromal composition of human uterine endometrium and endometrial tissue was characterized. Fibroblast-specific protein-1 was used for fibroblasts, smooth muscle actin alpha for myofibroblasts, and platelet-derived growth factor receptor beta (CD140b) for mesenchymal stromal cells (MSCs). The results demonstrated that the percentage of myofibroblasts was higher and the portion of MSCs was lower in ectopic endometrial stroma than those in eutopic endometrium. Moreover, the proportion of MSCs decreased significantly and the percentage of myofibroblasts increased considerably after FAC treatment in vitro. However, disruption of intracellular iron levels or ferroptosis via chelation of intracellular iron deferoxamine mesylate or ferroptosis inhibitor ferrostatin-1 could reverse this process, indicating that iron-induced ferroptosis plays a vital role in ovarian EMs fibrosis. Considering that iron accumulation can feed the Fenton reaction to generate unquenchable amounts of free radicals, causing ferroptosis and tissue damage and thereby contributing to fibrosis, we validated the underlying mechanism that excess iron can facilitate fibrotic responses. Collectively, these data provide evidence that supernumerary iron is a key regulator in promoting MSCs ferroptosis and inducing ovarian EMs fibrosis.

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“…Targeting specific DIE features, such as fibrosis, is of interest in future treatment research [ 16 , 17 ]. The heterogeneity of the ER-α and PR distribution could explain why endocrine treatments are unable to cure this condition and allow us to only stop progression [ 5 ].…”

Section: Pathophysiology Of Endometriosismentioning

confidence: 99%

“…Btk inhibitors have shown anti-tumor activity in animal models and in the clinic [ 110 ]. In in vitro studies, the signaling and metabolism of the bioactive sphingolipid sphingosine1 phosphate (S1P), which is involved in inflammation and the immune response, were altered in endometriosis and SIPR expression highlighted ovarian and deep endometriotic lesions [ 17 ]. S1P mediates TGFß1 fibrosis induction and modulation of S1P signaling could represent an innovative pharmacologic target for endometriosis.…”

Section: Non-hormonal Treatmentmentioning

confidence: 99%

New Therapeutics in Endometriosis: A Review of Hormonal, Non-Hormonal, and Non-Coding RNA Treatments

Brichant

Laraki

Henry

et al. 2021

IJMS

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Endometriosis is defined as endometrial-like tissue outside the uterine cavity. It is a chronic inflammatory estrogen-dependent disease causing pain and infertility in about 10% of women of reproductive age. Treatment nowadays consists of medical and surgical therapies. Medical treatments are based on painkillers and hormonal treatments. To date, none of the medical treatments have been able to cure the disease and symptoms recur as soon as the medication is stopped. The development of new biomedical targets, aiming at the cellular and molecular mechanisms responsible for endometriosis, is needed. This article summarizes the most recent medications under investigation in endometriosis treatment with an emphasis on non-coding RNAs that are emerging as key players in several human diseases, including cancer and endometriosis.

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Sphingosine 1-phosphate receptors are dysregulated in endometriosis: possible implication in transforming growth factor β–induced fibrosis

Cited by 25 publications

References 54 publications

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells

New Therapeutics in Endometriosis: A Review of Hormonal, Non-Hormonal, and Non-Coding RNA Treatments

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