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

Yuichi Ono ,Shuji Hirata,Junken Aoki,Takehiro Hiraoka,Kuniyuki Kano,Nobuya Unno,Yutaka Osuga,Shinichiro Wada,Akiko Furue,Kaori Koga,Masami Ito,Takeshi Iwasa,Takako Kawakita,Toshiaki Okuno,Takehiko Yokomizo,Erina Sato,Nobuyo Maeda ,Osamu Yokosuka ,Masashi Ohba ,Masahito Honda

doi:10.3390/biomedicines9111519

Abstract

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.

Highlights

Endometriosis is a problematic disease in women of reproductive age, of which the primary symptoms are infertility and pelvic pain [1,2]
When samples from all periods of the menstrual cycles were combined, there was no difference in Sphingosine 1-phosphate (S1P) concentration between the non-endometriosis (N = 19; 53.4 ± 13.0 nM; median 36.3 nM) and endometriosis (N = 14; 63.5 ± 8.7 nM; median 63.5 nM) patients (Figure 1b)
Focusing on a specific time of menstrual cycle, during the non-menstrual period, endometriosis patients showed a significant increase in S1P concentration (N = 10; 58.5 ± 10.0 nM; median 52.0 nM)

Summary

Introduction

Endometriosis is a problematic disease in women of reproductive age, of which the primary symptoms are infertility and pelvic pain [1,2]. Inflammation is known to be involved in the onset and progression of the disease [2,3]. We showed that aberrant secretion of inflammatory substances, such as prostaglandin, interleukin (IL)-1β, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1, play essential roles in the pathophysiology of Biomedicines 2021, 9, 1519. Endometriosis is recognized as a disease of inflammation, the starting point of inflammation is still not well-understood. To understand the mechanism of inflammation in the intra-peritoneal environment, it is essential to understand the role of immune cells in the intra-peritoneal cavity [6]. Among the different types of immune cells in the intra-peritoneal cavity, it is known that the number of macrophages (MΦ) is higher in patients with endometriosis [7].

Methods

Results

Conclusion