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

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.

[1]  S. Saito,et al.  CD206+ macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model , 2021, Scientific Reports.

[2]  S. Saito,et al.  CD206+ M2-Like Macrophages Are Essential for Successful Implantation , 2020, Frontiers in Immunology.

[3]  F. Petraglia,et al.  Sphingosine 1-phosphate receptors are dysregulated in endometriosis: possible implication in transforming growth factor β-induced fibrosis. , 2020, Fertility and sterility.

[4]  T. Onda,et al.  IL-33 Exacerbates Endometriotic Lesions via Polarizing Peritoneal Macrophages to M2 Subtype , 2020, Reproductive Sciences.

[5]  K. Ley,et al.  Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages , 2019, Front. Immunol..

[6]  T. Shima,et al.  Sphingosine 1 Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells , 2019, Reproductive Sciences.

[7]  Takako Kawakita,et al.  Intraperitoneal administration of activin A promotes development of endometriotic lesions in a mouse model of endometriosis. , 2019, Journal of Medical Investigation.

[8]  Robert N. Taylor,et al.  Endometriosis , 2018, Nature Reviews Disease Primers.

[9]  V. Natarajan,et al.  Targeting sphingosine-1-phosphate signaling in lung diseases. , 2016, Pharmacology & therapeutics.

[10]  Qi Zhang,et al.  Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial–mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation , 2016, Molecular and Cellular Endocrinology.

[11]  A. Fazleabas,et al.  Cellular Changes Consistent With Epithelial–Mesenchymal Transition and Fibroblast-to-Myofibroblast Transdifferentiation in the Progression of Experimental Endometriosis in Baboons , 2016, Reproductive Sciences.

[12]  K. Takabe,et al.  Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential , 2016, Mediators of inflammation.

[13]  M. Baranowski,et al.  Sources, metabolism, and regulation of circulating sphingosine-1-phosphate , 2015, Journal of Lipid Research.

[14]  S. Kyo,et al.  Possible involvement of signal transducer and activator of transcription-3 in cell-cell interactions of peritoneal macrophages and endometrial stromal cells in human endometriosis. , 2013, Fertility and sterility.

[15]  Annalisa Capobianco,et al.  Endometriosis, a disease of the macrophage , 2013, Front. Immun..

[16]  T. Kadowaki,et al.  Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. , 2012, Cell metabolism.

[17]  S. Milstien,et al.  The outs and the ins of sphingosine-1-phosphate in immunity , 2011, Nature Reviews Immunology.

[18]  Y. Taketani,et al.  Lymphocytes in Endometriosis , 2011, American journal of reproductive immunology.

[19]  S. Pyne,et al.  Sphingosine 1-phosphate and cancer , 2010, Nature Reviews Cancer.

[20]  S. Tsai,et al.  Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. , 2010, The American journal of pathology.

[21]  S. Ferrari,et al.  Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. , 2009, The American journal of pathology.

[22]  J. Donnez,et al.  Potential involvement of iron in the pathogenesis of peritoneal endometriosis. , 2008, Molecular human reproduction.

[23]  Y. Taketani,et al.  FR 167653, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis in a murine model. , 2006, Journal of reproductive immunology.

[24]  Yiling Lu,et al.  Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. , 2006, Cancer cell.

[25]  Y. Taketani,et al.  Possible Pathophysiological Roles of Mitogen‐Activated Protein Kinases (MAPKs) in Endometriosis , 2004, American journal of reproductive immunology.

[26]  Ming-Yih Wu,et al.  The Role of Cytokines in Endometriosis * , 2003, American journal of reproductive immunology.

[27]  J. Vena,et al.  Menstrual Cycle Characteristics and the Risk of Endometriosis , 1993, Epidemiology.

[28]  R. D'Amato,et al.  Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. , 2005, Fertility and sterility.