Stage-dependent sphingosine-1-phosphate pathway modulation as a therapeutic strategy in a murine model of adenomyosis

Marlyne Squatrito, Silvia Blacher, Julie Vervier, Laëtitia Bernet, Alessandra Camboni, Marie‐Madeleine Dolmans, Carine Munaut
Molecular human reproduction · 2026 · vol. 32(1) · doi:10.1093/molehr/gaag009 · PMID:41698850
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

This study found that S1P pathway modulation, particularly with SKI-5C, reduced lesion severity and altered immune cell profiles in a murine adenomyosis model, supporting its therapeutic potential.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

This study examined temporal regulation of sphingosine-1-phosphate (S1P) signaling in a tamoxifen-induced murine model of adenomyosis and tested whether pharmacological modulation changes uterine immune profiles and lesion severity. Using 122 female CD1 mice, the authors compared preventive FTY720 given at weaning versus therapeutic FTY720 or SKI-5C started at 6 weeks, assessing uterine weight, lesion prevalence and grading/depth, flow cytometry immune phenotyping, and uterine gene expression related to inflammation, angiogenesis, and invasion. Early disease (4 weeks) showed increased S1PR1/2 with downregulation of SGPL, while established disease (12 weeks) had sustained S1PR1 elevation with upregulation of SPHK1 and S1PR4; preventive FTY720 reduced lesion depth/grade and therapeutic SKI-5C reduced lesion prevalence/invasion, with immune-cell subset changes particularly for T- and NK-related subsets. Limitations included difficulty recovering immune cells from uterine tissue, relatively short treatment duration, and translational differences between mice and human adenomyosis. This paper is centrally about adenomyosis — it tests stage-dependent S1P pathway modulation (FTY720/SKI-5C) in a murine adenomyosis model and links it to immune remodeling and lesion progression.

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Abstract

Adenomyosis is characterized by chronic inflammation, myometrial remodeling, and subfertility, yet therapeutic options that preserve reproductive potential remain limited. Sphingosine-1-phosphate (S1P) signaling regulates immune-cell trafficking, vascular remodeling, and tissue invasion, but its contribution to adenomyosis remains poorly defined. This study investigated the temporal regulation of this pathway in a tamoxifen-induced murine model of adenomyosis and evaluated whether its pharmacological inhibition alters uterine immune profiles and lesion severity. A total of 122 female CD1 mice were used (79 adenomyosis, 43 control). Preventive treatment (with FTY720) started at weaning, while therapeutic interventions (with FTY720 and SKI-5C) were initiated at 6 weeks. Outcomes included body/uterine weight, lesion prevalence, grading and depth, immune-cell phenotyping by flow cytometry, and uterine expression of inflammatory, angiogenic, and invasion-associated genes. Early disease (at 4 weeks) was marked by increased expression of S1PR1/2 and downregulation of SGPL, while established disease (at 12 weeks) showed that S1PR1 remained elevated with additional upregulation of SPHK1 and S1PR4. Preventive FTY720 reduced lesion depth and grade, whereas therapeutic SKI-5C decreased lesion prevalence and invasion. Uterine weight remained reduced across adenomyosis groups and was not restored by treatment. Immune profiling revealed no major differences in total T-cell abundance between the control and adenomyosis groups. However, SKI-5C treatment was associated with the most pronounced modulation of uterine immune cells, particularly affecting T- and NK-cell-related subsets. Gene expression analyses demonstrated increased interleukin-6 in early disease and modulation of urokinase-type plasminogen activator associated with the treatments. Study limitations included constraints related to immune-cell recovery from uterine tissue, the relatively short duration of treatment, and translational differences between murine and human adenomyosis. Overall, these findings indicate that S1P signaling contributes to immune microenvironment remodeling and lesion progression in adenomyosis. These results support S1P pathway modulation as a promising therapeutic strategy meriting evaluation in human studies.
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Stage-dependent sphingosine-1-phosphate pathway modulation as a therapeutic strategy in a murine model of adenomyosis. (2026) Molecular Human Reproduction : basic science of reproductive medicine — Vol. 32, n° 1 (2026) (2026) Molecular Human Reproduction : basic science of reproductive medicine — Vol. 32, n° 1 (2026) Open Access - Adobe PDF - 1.98 MB - Authors - Author Squatrito, Marlyne - Author Blacher, Silvia - Author Vervier, Julie - Author Bernet, Laëtitia - Author Camboni, Alessandra UCLouvain - Author - Abstract - Adenomyosis is characterised by chronic inflammation, myometrial remodeling and subfertility, yet therapeutic options that preserve reproductive potential remain limited. Sphingosine-1-phosphate (S1P) signaling regulates immune-cell trafficking, vascular remodeling and tissue invasion, but its contribution in adenomyosis remains poorly defined. This study investigated the temporal regulation of this pathway in a tamoxifen-induced murine model of adenomyosis and evaluated whether its pharmacological inhibition alters uterine immune profiles and lesion severity. A total of 122 female CD1 mice were used (79 adenomyosis, 43 control). Preventive treatment (with FTY720) started at weaning, while therapeutic interventions (with FTY720 and SKI-5C) were initiated at 6 weeks. Outcomes included body/uterine weight, lesion prevalence, grading and depth, immune-cell phenotyping by flow cytometry, and uterine expression of inflammatory, angiogenic and invasion-associated genes. Early disease (at 4 weeks) was marked by increased expression of S1PR1/2 and downregulation of SGPL, while established disease (at 12 weeks) showed that S1PR1 remained elevated with additional upregulation of SPHK1 and S1PR4. Preventive FTY720 reduced lesion depth and grade, whereas therapeutic SKI-5C decreased lesion prevalence and invasion. Uterine weight remained reduced across adenomyosis groups and was not restored by treatment. Immune profiling revealed no major differences in total T-cell abundance between the control and adenomyosis groups. However, SKI-5C treatment was associated with the most pronounced modulation of uterine immune cells, particularly affecting T- and NK-cell-related subsets. Gene expression analyses demonstrated increased interleukin-6 in early disease and modulation of urokinase-type plasminogen activator associated with the treatments. Study limitations included constraints related to immune-cell recovery from uterine tissue, the relatively short duration of treatment, and translational differences between murine and human adenomyosis. Overall, these findings indicate that S1P signaling contributes to immune microenvironment remodeling and lesion progression in adenomyosis. These results support sphingosine-1-phosphate pathway modulation as a promising therapeutic strategy meriting evaluation in human studies. - Affiliations - APA - Chicago - FWB Squatrito, M., Blacher, S., Vervier, J., Bernet, L., Camboni, A., Dolmans, M.-M., & Munaut, C. (2026). Stage-dependent sphingosine-1-phosphate pathway modulation as a therapeutic strategy in a murine model of adenomyosis. Molecular Human Reproduction : basic science of reproductive medicine, 32(1). https://doi.org/10.1093/molehr/gaag009 (Original work published 2026)

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Condition tags

adenomyosis

MeSH descriptors

Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Fingolimod Hydrochloride Fingolimod Hydrochloride Fingolimod Hydrochloride Fingolimod Hydrochloride Fingolimod Hydrochloride Fingolimod Hydrochloride Fingolimod Hydrochloride

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SciLite annotations

chemicals 3
sphingosine sphingosine tamoxifen
organisms 3
mus sp. human human

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