Blocking sphingosine 1-phosphate receptor 1 with modulators reduces immune cells infiltration and alleviates endometriosis in mice

  • Reprod Biomed Online. 2023 Nov;47(5):103304. doi: 10.1016/j.rbmo.2023.103304.
Fengrui Zhang  1 ,  Mingyi Peng  1 ,  Xufen Zheng  2 ,  Xiaofang Wang  2 ,  Xiaoxiao Liu  2 ,  Chun Chen  3 ,  Yuan Lu  4
Affiliations
  • 1. Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Rd, Shanghai 200011, People's Republic of China.
  • 2. CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3. Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Rd, Shanghai 200011, People's Republic of China. Electronic address: [email protected].
  • 4. Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Rd, Shanghai 200011, People's Republic of China. Electronic address: [email protected].
PMID: 37757611 DOI: 10.1016/j.rbmo.2023.103304
Abstract

Research question: Do sphingosine 1-phosphate (S1P) modulators have therapeutic effects on endometriosis in mice and, if they do, which receptor is responsible for these effects?

Design: A surgically induced endometriosis mouse model was established. In the pilot experiment, lesions were harvested to assess fibrosis and inflammation and determine the optimal concentration of a broad-spectrum S1P modulator, FTY720. Subsequently, FTY720 was compared with a selective S1P receptor 1 modulator, SEW2871 to evaluate their effects on endometriotic lesion growth, fibrosis, inflammation and immune cell infiltration.

Results: The results demonstrated that both FTY720 and SEW2871, two S1P receptor modulators, effectively inhibited the growth and fibrosis of endometriotic lesions. SEW2871 inhibited inflammation-related cytokine expression, including PTGS-2, IL-1β, TNF-α and TGF-β1, more effectively compared with FTY720. Lymphopaenia was mainly caused by FTY720, whereas SEW2871 had a lesser effect. Both FTY720 and SEW2871 significantly reduced CD45+ cells (P = 0.002 and P = 0.032, respectively) and F4/80+ cells (P < 0.001 and P = 0.004, respectively) infiltration into the lesions, with FTY720 exerting a strong regulatory effect on CD4+ T cells.

Conclusions: This study suggests that S1P receptor 1 could be investigated as a potential novel therapeutic target for endometriosis in the future.

Keywords
S1PR modulator; endometriosis; fibrosis; immune cell; inflammation; macrophage.
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