外泌体通过调控免疫微环境治疗慢性子宫内膜炎的研究进展

doi:10.12280/gjfckx.20240908

摘要/Abstract

摘要：

慢性子宫内膜炎（chronic endometritis，CE）的病理特征为CD138+子宫内膜基质浆细胞异常浸润，这种持续的炎症状态可能会干扰免疫细胞浸润、细胞因子的表达以及子宫内膜蜕膜化进程，进而对胚胎植入产生负面影响，引起学者的广泛关注。外泌体（exosome）作为一种细胞间通讯的纳米级囊泡，目前已有较多的研究发现其在调控免疫微环境中显示出巨大潜力。综述外泌体在治疗CE中的研究进展，特别是其通过调控免疫改善内膜微环境的作用机制，这可能对CE治疗新方法起到指导作用。

关键词: 外泌体, 子宫内膜炎, 淋巴细胞, 细胞微环境, 胚胎植入, 治疗

Abstract:

Chronic endometritis (CE) is characterized by abnormal infiltration of CD138+ endometrial stromal plasma cells. This persistent inflammatory state can disrupt immune cell infiltration, cytokine expression, and endometrial decidualization, negatively impacting embryo implantation and attracting significant research interest. Exosomes, nano-sized vesicles mediating intercellular communication, have shown considerable promise in modulating the immune microenvironment. This review summarizes the progress of exosome-based therapies for CE, focusing on their mechanism of action in improving the endometrial microenvironment through immune modulation. This may guide the development of novel therapeutic strategies for CE.

Key words: Exosomes, Endometritis, Lymphocytes, Cellular microenvironment, Embryo implantation, Therapy

李恒兵, 袁海宁, 张云洁, 张江琳, 郭子珍, 孙振高. 外泌体通过调控免疫微环境治疗慢性子宫内膜炎的研究进展[J]. 国际妇产科学杂志, 2025, 52(1): 72-78.

LI Heng-bing, YUAN Hai-ning, ZHANG Yun-jie, ZHANG Jiang-lin, GUO Zi-zhen, SUN Zhen-gao. Advances in Exosome-Based Therapy for Chronic Endometritis by Modulating the Immune Microenvironment[J]. Journal of International Obstetrics and Gynecology, 2025, 52(1): 72-78.

参考文献 41

[1]	Yasuo T, Kitaya K. Challenges in Clinical Diagnosis and Management of Chronic Endometritis[J]. Diagnostics(Basel), 2022, 12(11):2711. doi: 10.3390/diagnostics12112711.
[2]	Kitaya K, Takeuchi T, Mizuta S, et al. Endometritis: new time, new concepts[J]. Fertil Steril, 2018, 110(3):344-350. doi: 10.1016/j.fertnstert.2018.04.012. pmid: 29960704
[3]	Cicinelli E, Cicinelli R, Vitagliano A. Consistent evidence on the detrimental role of severe chronic endometritis on in vitro fertilization outcome and the reproductive improvement after antibiotic therapy: on the other hand, mild chronic endometritis appears a more intricate matter[J]. Fertil Steril, 2021, 116(2):345-346. doi: 10.1016/j.fertnstert.2021.06.022.
[4]	Hassaan NA, Mansour HA. Exosomal therapy is a luxury area for regenerative medicine[J]. Tissue Cell, 2024,91:102570. doi: 10.1016/ j.tice.2024.102570.
[5]	Agarwal P, Anees A, Harsiddharay RK, et al. A Comprehensive Review on Exosome: Recent Progress and Outlook[J]. Pharm Nanotechnol,2023 May 23. doi: 10.2174/2211738511666230523114311.Epub ahead of print.
[6]	Yang L, Su Y, Cai S, et al. Regional Analysis of the Immune Microenvironment in Human Endometrium[J]. Am J Reprod Immunol, 2024, 92(3):e13921. doi: 10.1111/aji.13921.
[7]	Brown E, Martínez-Aguilar R, Maybin JA, et al. Endometrial macrophages in health and disease[J]. Int Rev Cell Mol Biol, 2022, 367:183-208. doi: 10.1016/bs.ircmb.2022.03.011. pmid: 35461658
[8]	Marron K, Harrity C. Potential utility of a non-invasive menstrual blood immunophenotype analysis in reproductive medicine[J]. Reprod Fertil, 2022, 3(4):255-261. doi: 10.1530/RAF-22-0047.
[9]	Schulke L, Manconi F, Markham R, et al. Endometrial dendritic cell populations during the normal menstrual cycle[J]. Hum Reprod, 2008, 23(7):1574-1580. doi: 10.1093/humrep/den030.
[10]	Díaz-Hernández I, Alecsandru D, García-Velasco JA, et al. Uterine natural killer cells: from foe to friend in reproduction[J]. Hum Reprod Update, 2021, 27(4):720-746. doi: 10.1093/humupd/dmaa062. pmid: 33528013
[11]	Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions[J]. Immunity, 2010, 32(5):593-604. doi: 10.1016/j.immuni.2010.05.007. pmid: 20510870
[12]	Di Vincenzo S, Ferraro M, Taverna S, et al. Tyndallized Bacteria Preferentially Induce Human Macrophage M1 Polarization: An Effect Useful to Balance Allergic Immune Responses and to Control Infections[J]. Antibiotics(Basel), 2023, 12(3):571. doi: 10.3390/antibiotics12030571.
[13]	Wang LL, Li ZH, Wang H, et al. Cutting edge: the regulatory mechanisms of macrophage polarization and function during pregnancy[J]. J Reprod Immunol, 2022,151:103627. doi: 10.1016/j.jri.2022.103627.
[14]	Luo W, Hoang H, Miller KE, et al. Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning "Two Keys" simultaneously[J]. J Exp Clin Cancer Res, 2024, 43(1):193. doi: 10.1186/s13046-024-03093-w. pmid: 38992659
[15]	Kang S, Jin S, Mao X, et al. CD4⁺T and CD8⁺T Cells in Uterus Exhibit Both Selective Dysfunction and Residency Signatures[J]. J Immunol Res, 2024,2024:5582151. doi: 10.1155/2024/5582151.
[16]	Rao VA, Kurian NK, Rao KA. Cytokines, NK cells and regulatory T cell functions in normal pregnancy and reproductive failures[J]. Am J Reprod Immunol, 2023, 89(2):e13667. doi: 10.1111/aji.13667.
[17]	Shen M, O′Donnell E, Leon G, et al. The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review[J]. Hum Reprod Open, 2022, 2022(1):hoab043. doi: 10.1093/hropen/hoab043.
[18]	Shen M, Child T, Mittal M, et al. B Cell Subset Analysis and Gene Expression Characterization in Mid-Luteal Endometrium[J]. Front Cell Dev Biol, 2021,9:709280. doi: 10.3389/fcell.2021.709280.
[19]	Bora M, Singha S, Madan T, et al. HLA-G isoforms, HLA-C allotype and their expressions differ between early abortus and placenta in relation to spontaneous abortions[J]. Placenta, 2024, 149:44-53. doi: 10.1016/j.placenta.2024.02.009. pmid: 38492472
[20]	Pirtea P, Cicinelli E, De Nola R, et al. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis[J]. Fertil Steril, 2021, 115(3):546-560. doi: 10.1016/j.fertnstert.2020.12.010. pmid: 33581856
[21]	Kitazawa J, Kimura F, Nakamura A, et al. Alteration in endometrial helper T-cell subgroups in chronic endometritis[J]. Am J Reprod Immunol, 2021, 85(3):e13372. doi: 10.1111/aji.13372.
[22]	Li Y, Yu S, Huang C, et al. Evaluation of peripheral and uterine immune status of chronic endometritis in patients with recurrent reproductive failure[J]. Fertil Steril, 2020, 113(1):187-196.e1. doi: 10.1016/j.fertnstert.2019.09.001. pmid: 31718829
[23]	Chen X, Liu Y, Zhao Y, et al. Association between chronic endometritis and uterine natural killer cell density in women with recurrent miscarriage: clinical implications[J]. J Obstet Gynaecol Res, 2020, 46(6):858-863. doi: 10.1111/jog.14250.
[24]	Wang WJ, Zhang H, Chen ZQ, et al. Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis[J]. Reprod Biol Endocrinol, 2019, 17(1):2. doi: 10.1186/s12958-018-0444-9.
[25]	Driva TS, Schatz C, M, et al. The Role of mTOR and eIF Signaling in Benign Endometrial Diseases[J]. Int J Mol Sci, 2022, 23(7):3416. doi: 10.3390/ijms23073416.cˇSoboan
[26]	Zeng S, Liu X, Liu D, et al. Research update for the immune microenvironment of chronic endometritis[J]. J Reprod Immunol, 2022,152:103637. doi: 10.1016/j.jri.2022.103637.
[27]	Muter J, Lynch VJ, McCoy RC, et al. Human embryo implantation[J]. Development, 2023, 150(10):dev201507. doi: 10.1242/dev.201507.
[28]	Pan Z, Zhao R, Li B, et al. EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3[J]. Mol Cancer, 2022, 21(1):16. doi: 10.1186/s12943-021-01485-6. pmid: 35031058
[29]	Zhang Y, Zhu L, Li X, et al. M2 macrophage exosome-derived lncRNA AK083884 protects mice from CVB3-induced viral myocarditis through regulating PKM2/HIF-1α axis mediated metabolic reprogramming of macrophages[J]. Redox Biol, 2024,69:103016. doi: 10.1016/j.redox.2023.103016.
[30]	Yan Q, Song C, Liu H, et al. Adipose-derived stem cell exosomes loaded with icariin attenuated M1 polarization of macrophages via inhibiting the TLR4/Myd88/NF-κB signaling pathway[J]. Int Immunopharmacol, 2024,137:112448. doi: 10.1016/j.intimp.2024.112448.
[31]	Fang Z, Mao J, Huang J, et al. Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice[J]. Cell Commun Signal, 2024, 22(1):230. doi: 10.1186/s12964-024-01610-0. pmid: 38627796
[32]	Wang R, Li R, Li T, et al. Bone Mesenchymal Stem Cell-Derived Exosome-Enclosed miR-181a Induces CD4⁺CD25⁺FOXP3⁺ Regulatory T Cells via SIRT1/Acetylation-Mediated FOXP3 Stabilization[J]. J Oncol, 2022,2022:8890434. doi: 10.1155/2022/8890434.
[33]	Taravat M, Asadpour R, Jozani RJ, et al. Enhanced anti-inflammatory effect of Rosmarinic acid by encapsulation and combination with the exosome in mice with LPS-induced endometritis through suppressing the TLR4-NLRP3 signaling pathway[J]. J Reprod Immunol, 2023, 159:103992. doi: 10.1016/j.jri.2023.103992.
[34]	Taravat M, Asadpour R, Jafari Jozani R, et al. Engineered exosome as a biological nanoplatform for drug delivery of Rosmarinic acid to improve implantation in mice with induced endometritis[J]. Syst Biol Reprod Med, 2024, 70(1):3-19. doi: 10.1080/19396368.2024.2306420. pmid: 38323586
[35]	Chen Y, Zheng S, Zhao X, et al. Unveiling the protective effects of BMSCs/anti-miR-124-3p exosomes on LPS-induced endometrial injury[J]. Funct Integr Genomics, 2024, 24(2):32. doi: 10.1007/s10142-024-01303-4.
[36]	Wang B, Li L, Yu R. Exosomes From Adipose-Derived Stem Cells Suppress the Progression of Chronic Endometritis[J]. Cell Transplant, 2023,32:9636897231173736. doi: 10.1177/09636897231173736.
[37]	Zhao C, Li J, Cai H, et al. An injectable hydrogel scaffold with IL-1β-activated MSC-derived exosomes for the treatment of endometritis[J]. Biomater Sci, 2023, 11(4):1422-1436. doi: 10.1039/d2bm01586b.
[38]	Wang X, Tian F, Chen C, et al. Exosome-derived uterine microRNAs isolated from cows with endometritis impede blastocyst development[J]. Reprod Biol, 2019, 19(2):204-209. doi: 10.1016/j.repbio.2019.06.003. pmid: 31196738
[39]	Wang X, Yao X, Xie T, et al. Exosome-derived uterine miR-218 isolated from cows with endometritis regulates the release of cytokines and chemokines[J]. Microb Biotechnol, 2020, 13(4):1103-1117. doi: 10.1111/1751-7915.13565. pmid: 32227590
[40]	Wang X, Li Q, Xie T, et al. Exosomes from bovine endometrial epithelial cells ensure trophoblast cell development by miR-218 targeting secreted frizzled related protein 2[J]. J Cell Physiol, 2021, 236(6):4565-4579. doi: 10.1002/jcp.30180. pmid: 33230823
[41]	Jiang K, Chen Y, Wang K, et al. miR-331-depleted exosomes derived from injured endometrial epithelial cells promote macrophage activation during endometritis[J]. Int J Biol Macromol, 2024, 279(Pt 4):134967. doi: 10.1016/j.ijbiomac.2024.134967.