Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis
Chronic endometritis (CE) is an inflammatory disease of the uterus that is associated with infertility and poor reproductive outcomes. Although most cases of CE are attributed to bacterial infections, antibiotic treatment is sometimes ineffective, and the mechanisms underlying the development and pe...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1547949/full |
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| author | Shigeru Matsuda Yoshimitsu Kuwabara Yoshitaka Taketomi Yuki Nagasaki Yosuke Sugita Shunji Suzuki Ichiro Manabe Makoto Murakami Yumiko Oishi |
| author_facet | Shigeru Matsuda Yoshimitsu Kuwabara Yoshitaka Taketomi Yuki Nagasaki Yosuke Sugita Shunji Suzuki Ichiro Manabe Makoto Murakami Yumiko Oishi |
| author_sort | Shigeru Matsuda |
| collection | DOAJ |
| description | Chronic endometritis (CE) is an inflammatory disease of the uterus that is associated with infertility and poor reproductive outcomes. Although most cases of CE are attributed to bacterial infections, antibiotic treatment is sometimes ineffective, and the mechanisms underlying the development and persistence of inflammation in CE are poorly understood. In the present study, we established a novel mouse model of CE that causes fetal death without affecting implantation and demonstrated that dysregulation of lipid metabolism contributes to its pathology. A deficiency in SREBP1, a key regulator of lipid metabolism, prolonged endometrial inflammation with CD138+ plasma cell accumulation and induced miscarriage in LPS-induced endometritis, thereby mimicking CE. Lipidomic analyses showed that Srebf1 deficiency significantly reduced phospholipids containing eicosapentaenoic acid (EPA) within uterine tissue. Dietary supplementation of EPA increased endometrial levels of EPA-containing phospholipids and ameliorated inflammation and miscarriage in Srebf1-/- CE mice. These results suggest that dysregulation of lipid metabolism, particularly reductions in polyunsaturated fatty acids in endometrial phospholipids, promotes inflammation and miscarriage in CE. Importantly, EPA-containing phospholipids were also decreased in endometrial tissue from human CE patients. Thus, dysregulated lipid metabolism appears to play a pivotal role in the development of CE and provides novel therapeutic targets. |
| format | Article |
| id | doaj-art-77220fdebf0d43f787dd014a980aa2d1 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-77220fdebf0d43f787dd014a980aa2d12025-08-20T03:07:51ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15479491547949Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritisShigeru Matsuda0Yoshimitsu Kuwabara1Yoshitaka Taketomi2Yuki Nagasaki3Yosuke Sugita4Shunji Suzuki5Ichiro Manabe6Makoto Murakami7Yumiko Oishi8Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, JapanDepartment of Obstetrics and Gynecology, Nippon Medical School, Tokyo, JapanLaboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanLaboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Obstetrics and Gynecology, Nippon Medical School, Tokyo, JapanDepartment of Obstetrics and Gynecology, Nippon Medical School, Tokyo, JapanDepartment of Systems Medicine, Graduate School of Medicine, Chiba University, Chiba, JapanLaboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, JapanChronic endometritis (CE) is an inflammatory disease of the uterus that is associated with infertility and poor reproductive outcomes. Although most cases of CE are attributed to bacterial infections, antibiotic treatment is sometimes ineffective, and the mechanisms underlying the development and persistence of inflammation in CE are poorly understood. In the present study, we established a novel mouse model of CE that causes fetal death without affecting implantation and demonstrated that dysregulation of lipid metabolism contributes to its pathology. A deficiency in SREBP1, a key regulator of lipid metabolism, prolonged endometrial inflammation with CD138+ plasma cell accumulation and induced miscarriage in LPS-induced endometritis, thereby mimicking CE. Lipidomic analyses showed that Srebf1 deficiency significantly reduced phospholipids containing eicosapentaenoic acid (EPA) within uterine tissue. Dietary supplementation of EPA increased endometrial levels of EPA-containing phospholipids and ameliorated inflammation and miscarriage in Srebf1-/- CE mice. These results suggest that dysregulation of lipid metabolism, particularly reductions in polyunsaturated fatty acids in endometrial phospholipids, promotes inflammation and miscarriage in CE. Importantly, EPA-containing phospholipids were also decreased in endometrial tissue from human CE patients. Thus, dysregulated lipid metabolism appears to play a pivotal role in the development of CE and provides novel therapeutic targets.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1547949/fullPUFAEPAchronic endometritisinfertility treatmentreccurrent pregnancy loss |
| spellingShingle | Shigeru Matsuda Yoshimitsu Kuwabara Yoshitaka Taketomi Yuki Nagasaki Yosuke Sugita Shunji Suzuki Ichiro Manabe Makoto Murakami Yumiko Oishi Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis Frontiers in Immunology PUFA EPA chronic endometritis infertility treatment reccurrent pregnancy loss |
| title | Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis |
| title_full | Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis |
| title_fullStr | Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis |
| title_full_unstemmed | Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis |
| title_short | Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis |
| title_sort | impaired srebp1 mediated regulation of lipid metabolism promotes inflammation in chronic endometritis |
| topic | PUFA EPA chronic endometritis infertility treatment reccurrent pregnancy loss |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1547949/full |
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