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山东大学学报 (医学版) ›› 2021, Vol. 59 ›› Issue (8): 8-13.doi: 10.6040/j.issn.1671-7554.0.2021.0958

• 生殖免疫的基础与临床研究进展专题 • 上一篇    下一篇

NK细胞参与子宫内膜异位症及其不孕的分子机制

单婧,王晓秋,李大金*()   

  1. 复旦大学附属妇产科医院研究所,上海 200090
  • 收稿日期:2021-08-12 出版日期:2021-08-10 发布日期:2021-09-16
  • 通讯作者: 李大金 E-mail:djli@shmu.edu.cn
  • 作者简介:李大金,博士,教授,博士研究生导师,国家973计划首席科学家。长期从事生殖免疫相关的临床和基础研究,先后在《Blood》《Autophagy》等权威期刊发表学术论文200余篇,主持国家重大研究计划、国家自然科学基金重点项目等国家级项目和国际合作项目20余项。先后获中华医学科技奖二等奖、上海医学科技奖二等奖、教育部科技进步二等奖、美洲生殖免疫学会杰出成就奖。现任中国免疫学会生殖免疫分会主委、美国生殖免疫学会副主席和美国生殖免疫学杂志编委
  • 基金资助:
    国家自然科学基金(81971456);国家自然科学基金(32070915)

Molecular mechanisms of NK cells involved in endometriosis and its associated infertility

Jing SHAN,Xiaoqiu WANG,Dajin LI*()   

  1. Institute of Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
  • Received:2021-08-12 Online:2021-08-10 Published:2021-09-16
  • Contact: Dajin LI E-mail:djli@shmu.edu.cn

摘要:

NK细胞作为机体免疫系统的第一道防线,参与多种自身免疫性疾病、感染性疾病以及肿瘤等疾病的发生发展。不同活化状态的NK细胞具有不同的免疫效应,与疾病的转归密切相关。子宫内膜异位症(EMS)是一种常见的妇科疾病,虽为良性病变,但子宫内膜异位种植生长的特性与肿瘤相似,且受损的在位子宫内膜与胚胎着床失败相关,是EMS相关不孕的重要病因。虽然目前已明确异位灶微环境免疫失调是促进异位灶种植生长的重要因素,且NK细胞是异位灶异常免疫微环境形成的关键细胞,但深入的致病机制及其在位子宫内膜损伤的分子机制仍然知之甚少。本文梳理了近年来NK细胞参与EMS发病的相关研究,以期更好地理解EMS及EMS相关不孕的发病机制,为EMS的防治及EMS相关不孕的诊治提供新思路。

关键词: NK细胞, 子宫内膜异位症, 异位灶微环境, 不孕

Abstract:

As the first line of defense of the immune system, NK cells are involved in the occurrence and development of a variety of autoimmune diseases, infectious diseases, and tumors. NK cells in different states of activation have different functions, which are closely related to the outcome of the disease. Although endometriosis (EMS) is a common and benign gynecological disease, the growth characteristics of ectopic foci are similar to tumors, and the damaged eutopic endometrium is associated with abnormal embryo implantation, which is an important cause of EMS-related infertility. Although it has been established that the abnormal immune microenvironment is an important factor promoting the growth of ectopic foci, and NK cells are the key cells in ectopic milieu, the in-depth functional regulation mechanism and its potential role played in endometrial injury are still poorly understood. This article updates the research progress of NK cells in the pathogenesis of EMS, in order to provide better understanding of the pathogenesis of EMS and EMS-related infertility, and new ideas for the prevention, diagnosis and treatment of EMS and EMS-related infertility.

Key words: NK cells, Endometriosis, Ectopic milieu, Infertility

中图分类号: 

  • R711.71
1 Bulun SE . Mechanisms of disease endometriosis[J]. N Engl J Med, 2009, 360 (3): 268- 279.
doi: 10.1056/NEJMra0804690
2 Burney RO , Giudice LC . Pathogenesis and pathophysiology of endometriosis[J]. Fertil Steril, 2012, 98 (3): 511- 519.
doi: 10.1016/j.fertnstert.2012.06.029
3 Kyama C , Debrock S , Mwenda JM , et al. Potential involvement of the immune system in the development of endometriosis[J]. Reprod Biol Endocrin, 2003, 1, 123.
doi: 10.1186/1477-7827-1-123
4 Hassa H , Tanir HM , Tekin B , et al. Cytokine and immune cell levels in peritoneal fluid and peripheral blood of women with early- and late-staged endometriosis[J]. Arch Gynecol Obstet, 2009, 279 (6): 891- 895.
doi: 10.1007/s00404-008-0844-8
5 Nothnick WB . Treating endometriosis as an autoimmune disease[J]. Fertil Steril, 2001, 76 (2): 223- 231.
doi: 10.1016/S0015-0282(01)01878-7
6 Vivier E , Tomasello E , Baratin M , et al. Functions of natural killer cells[J]. Nat Immunol, 2008, 9 (5): 503- 510.
doi: 10.1038/ni1582
7 Caligiuri MA . Human natural killer cells[J]. Blood, 2008, 112 (3): 461- 469.
doi: 10.1182/blood-2007-09-077438
8 Chou YC , Chen CH , Chen MJ , et al. Killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C) allorecognition patterns in women with endometriosis[J]. Sci Rep, 2020, 10 (1): 4897.
doi: 10.1038/s41598-020-61702-y
9 Dias JA , Podgaec S , de Oliveira RM , et al. Patients with endometriosis of the rectosigmoid have a higher percentage of natural killer cells in peripheral blood[J]. J Minim Invasive Gynecol, 2012, 19 (3): 317- 324.
doi: 10.1016/j.jmig.2011.12.021
10 Mei J , Zhou WJ , Zhu XY , et al. Suppression of autophagy and HCK signaling promotes PTGS2(high) FCGR3(-) NK cell differentiation triggered by ectopic endometrial stromal cells[J]. Autophagy, 2018, 14 (8): 1376- 1397.
doi: 10.1080/15548627.2018.1476809
11 Maeda N , Izumiya C , Yamamoto Y , et al. Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis[J]. Fertil Steril, 2002, 77 (2): 297- 302.
doi: 10.1016/S0015-0282(01)02964-8
12 Xu H . Expressions of natural cytotoxicity receptor, NKG2D and NKG2D ligands in endometriosis[J]. J Reprod Immunol, 2019, 136, 102615.
doi: 10.1016/j.jri.2019.102615
13 Funamizu A , Fukui A , Kamoi M , et al. Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis[J]. Am J Reprod Immunol, 2014, 71 (4): 359- 367.
doi: 10.1111/aji.12206
14 Vivier E , Nunes JA , Vely F . Natural killer cell signaling pathways[J]. Science, 2004, 306 (5701): 1517- 1519.
doi: 10.1126/science.1103478
15 Marçais A , Marotel M , Degouve S , et al. High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors[J]. Elife, 2017, 6, 264.
doi: 10.7554/eLife.26423
16 Souza-Fonseca-Guimaraes F , Adib-Conquy M , Cavaillon JM . Natural killer (NK) cells in antibacterial innate immunity: angels or devils?[J]. Mol Med, 2012, 18, 270- 285.
doi: 10.2119/molmed.2011.00201
17 Viel S , Mar ç ais A , Guimaraes F , et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway[J]. Sci Signal, 2016, 9 (415): ra19.
doi: 10.1126/scisignal.aad1884
18 Oosterlynck DJ , Meuleman C , Waer M , et al. Immunosuppressive activity of peritoneal fluid in women with endometriosis[J]. Obstet Gynecol, 1993, 82 (2): 206- 212.
19 Yang HL , Zhou WJ , Chang KK , et al. The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-beta[J]. Reproduction, 2017, 154 (6): 815- 825.
doi: 10.1530/REP-17-0342
20 Guo SW , Du Y , Liu X . Platelet-derived TGF-beta1 mediates the down-modulation of NKG2D expression and may be responsible for impaired natural killer (NK) cytotoxicity in women with endometriosis[J]. Hum Reprod, 2016, 31 (7): 1462- 1474.
doi: 10.1093/humrep/dew057
21 Kang YJ , Jeung IC , Park A , et al. An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression[J]. Hum Reprod, 2014, 29 (10): 2176- 2189.
doi: 10.1093/humrep/deu172
22 Zhang B , Zhou WJ , Gu CJ , et al. The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity[J]. Cell Death Dis, 2018, 9 (5): 574.
doi: 10.1038/s41419-018-0581-2
23 Terren I , Orrantia A , Vitalle J , et al. NK cell metabolism and tumor microenvironment[J]. Front Immunol, 2019, 10, 2278.
doi: 10.3389/fimmu.2019.02278
24 Parodi M , Raggi F , Cangelosi D , et al. Hypoxia modifies the transcriptome of human NK cells, modulates their immunoregulatory Profile, and Influences NK Cell Subset Migration[J]. Front Immunol, 2018, 9, 2358.
doi: 10.3389/fimmu.2018.02358
25 Assmann N , O'brien KL , Donnelly RP , et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses[J]. Nat Immunol, 2017, 18 (11): 1197- 1206.
doi: 10.1038/ni.3838
26 Simopoulou M , Rapani A , Grigoriadis S , et al. Getting to know endometriosis-related infertility better: a review on how endometriosis affects oocyte quality and embryo development[J]. Biomedicines, 2021, 9 (3): 273.
doi: 10.3390/biomedicines9030273
27 Indra DH , Diana A , Antonio GVJ , 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
28 Huhn O , Zhao XH , Esposito L , et al. How do uterine natural killer and innate lymphoid cells contribute to successful pregnancy?[J]. Front Immunol, 2021, 12, 607669.
doi: 10.3389/fimmu.2021.607669
29 Fu BQ , Zhou YG , Ni X , et al. Natural killer cells promote fetal development through the secretion of growth-promoting factors[J]. Immunity, 2017, 47 (6): 1100- 1113.
doi: 10.1016/j.immuni.2017.11.018
30 Matsubayashi H , Hosaka T , Sugiyama Y , et al. Increased natural killer-cell activity is associated with infertile women[J]. Am J Reprod Immunol, 2001, 46 (5): 318- 322.
doi: 10.1034/j.1600-0897.2001.d01-18.x
31 Giuliani E , Parkin KL , Lessey BA , et al. Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis[J]. Am J Reprod Immunol, 2014, 72 (3): 262- 269.
doi: 10.1111/aji.12259
32 Junovich G , Azpiroz A , Incera E , et al. Endometrial CD16(+) and CD16(-) NK cell count in fertility and unexplained infertility[J]. Am J Reprod Immunol, 2013, 70 (3): 182- 189.
doi: 10.1111/aji.12132
33 Drury JA , Parkin KL , Coyne L , et al. The dynamic changes in the number of uterine natural killer cells are specific to the eutopic but not to the ectopic endometrium in women and in a baboon model of endometriosis[J]. Reprod Biol Endocrin, 2018, 16 (1): 67.
doi: 10.1186/s12958-018-0385-3
34 Takeyama R , Fukui A , Mai C , et al. Co-expression of NKp46 with activating or inhibitory receptors on, and cytokine production by, uterine endometrial NK cells in recurrent pregnancy loss[J]. J Reprod Immunol, 2021, 145, 103324.
doi: 10.1016/j.jri.2021.103324
35 Fukui A , Funamizu A , Yokota M , et al. Uterine and circulating natural killer cells and their roles in women with recurrent pregnancy loss, implantation failure and preeclampsia[J]. J Reprod Immunol, 2011, 90 (1): 105- 110.
doi: 10.1016/j.jri.2011.04.006
36 Kotlyar A , Taylor HS , D'Hooghe TM . Use of immunomodulators to treat endometriosis[J]. Best Pract Res Clin Obstet Gynaecol, 2019, 60, 56- 65.
doi: 10.1016/j.bpobgyn.2019.06.006
37 Velasco I , Quereda F , Bermejo R , et al. Intraperitoneal recombinant interleukin-2 activates leukocytes in rat endometriosis[J]. J Reprod Immunol, 2007, 74 (1-2): 124- 132.
doi: 10.1016/j.jri.2006.12.001
38 Acien P , Velasco I , Acien M , et al. Treatment of endometriosis with transvaginal ultrasound-guided drainage and recombinant interleukin-2 left in the cysts: a third clinical trial[J]. Gynecol Obstet Invest, 2010, 69 (3): 203- 211.
doi: 10.1159/000270901
39 Ata B , Tan SL , Shehata F , et al. A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage[J]. Fertil Steril, 2011, 95 (3): 1080- U296.
doi: 10.1016/j.fertnstert.2010.12.021
40 Roussev RG , Ng SC , Coulam CB . Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G[J]. Am J Reprod Immunol, 2007, 57 (4): 262- 269.
doi: 10.1111/j.1600-0897.2007.00473.x
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