NLRP3 inflammasome is involved in uterine activation for labor at term and preterm

in Reproduction
View More View Less
  • 1 Department of Gynecology and Obstetrics, Xiangya Hospital Central South University, Changsha, China
  • | 2 National International Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha, China
  • | 3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
  • | 4 Department of Physiology, Navy Medical University, Shanghai, China
  • | 5 Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
  • | 6 Medical School of Shanghai University, Shanghai, China
  • | 7 Department of Gynecology and Obstetrics, Changhai Hospital, Shanghai, China

Correspondence should be addressed to X Ni; Email: xinni2018@csu.edu.cn

*(Z Chen and Y Shan contributed equally to this work)

Restricted access

The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases. We sought to investigate the role of NLRP3 inflammasome in uterine activation for labor at term and preterm. We found that NLRP3 inflammasome was activated in the myometrium tissues obtained from the pregnant women undergoing labor at term (TL) compared with those not undergoing labor (TNL) at term. NLRP3 inflammasome was also activated in amnion and chorion-deciduas in TL and preterm labor (PTL) groups. In the mouse model, uterine NLRP3 inflammasome and nuclear factor kappaB (NF-κB) were activated toward term and during labor. Treatment of pregnant mice with lipopolysaccharide (LPS) and RU38486 induced preterm birth (PTB) and also promoted uterine NLRP3 inflammasome and NF-κB activation. Treatment of pregnant mice with NLRP3 inflammasome inhibitor BAY11-7082 and MCC950 delayed the onset of labor and suppressed NLRP3 inflammasome and NF-κB activation in uterus. MCC950 postponed labor onset of the mice with LPS and RU38486 treatment and inhibited NLRP3 inflammasome activation in uterus. Our data provide the evidence that NLRP3 inflammasome is involved in uterine activation for labor onset in term and PTB in humans and mouse model.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 462 462 338
Full Text Views 24 24 17
PDF Downloads 30 30 20
  • Agrawal V & Hirsch E 2012 Intrauterine infection and preterm labor. Seminars in Fetal and Neonatal Medicine 17 1219. (https://doi.org/10.1016/j.siny.2011.09.001)

    • Search Google Scholar
    • Export Citation
  • Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG & Stutz A et al.2015 A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine 21 248255. (https://doi.org/10.1038/nm.3806)

    • Search Google Scholar
    • Export Citation
  • Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, Chitty JL, Fraser JA, Jennings MP & Robertson AAB et al.2019 MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nature Chemical Biology 15 556559. (https://doi.org/10.1038/s41589-019-0277-7)

    • Search Google Scholar
    • Export Citation
  • Conley AJ & Ball BA 2019 Steroids in the establishment and maintenance of pregnancy and at parturition in the mare. Reproduction 158 R197R208. (https://doi.org/10.1530/REP-19-0179)

    • Search Google Scholar
    • Export Citation
  • Di Renzo GC, Tosto V & Giardina I 2018 The biological basis and prevention of preterm birth. Best Practice and Research: Clinical Obstetrics and Gynaecology 52 1322. (https://doi.org/10.1016/j.bpobgyn.2018.01.022)

    • Search Google Scholar
    • Export Citation
  • Dudley DJ, Branch DW, Edwin SS & Mitchell MD 1996 Induction of preterm birth in mice by RU486. Biology of Reproduction 55 992995. (https://doi.org/10.1095/biolreprod55.5.992)

    • Search Google Scholar
    • Export Citation
  • Faro J, Romero R, Schwenkel G, Garcia-Flores V, Arenas-Hernandez M, Leng Y, Xu Y, Miller D, Hassan SS & Gomez-Lopez N 2019 Intra-amniotic inflammation induces preterm birth by activating the NLRP3 inflammasome. Biology of Reproduction 100 12901305. (https://doi.org/10.1093/biolre/ioy261)

    • Search Google Scholar
    • Export Citation
  • Gilman-Sachs A, Dambaeva S, Salazar Garcia MD, Hussein Y, Kwak-Kim J & Beaman K 2018 Inflammation induced preterm labor and birth. Journal of Reproductive Immunology 129 5358. (https://doi.org/10.1016/j.jri.2018.06.029)

    • Search Google Scholar
    • Export Citation
  • Goldenberg RL, Culhane JF, Iams JD & Romero R 2008 Epidemiology and causes of preterm birth. Lancet 371 7584. (https://doi.org/10.1016/S0140-6736(0860074-4)

    • Search Google Scholar
    • Export Citation
  • Gomez-Lopez N, StLouis D, Lehr MA, Sanchez-Rodriguez EN & Arenas-Hernandez M 2014 Immune cells in term and preterm labor. Cellular and Molecular Immunology 11 571581. (https://doi.org/10.1038/cmi.2014.46)

    • Search Google Scholar
    • Export Citation
  • Gomez-Lopez N, Romero R, Xu Y, Plazyo O, Unkel R, Leng Y, Than NG, Chaiworapongsa T, Panaitescu B & Dong Z et al.2017 A role for the inflammasome in spontaneous preterm labor with acute histologic chorioamnionitis. Reproductive Science 24 13821401. (https://doi.org/10.1177/1933719116687656)

    • Search Google Scholar
    • Export Citation
  • Gomez-Lopez N, Romero R, Panaitescu B, Leng Y, Xu Y, Tarca AL, Faro J, Pacora P, Hassan SS & Hsu CD 2018 Inflammasome activation during spontaneous preterm labor with intra-amniotic infection or sterile intra-amniotic inflammation. American Journal of Reproductive Immunology 80 e13049. (https://doi.org/10.1111/aji.13049)

    • Search Google Scholar
    • Export Citation
  • Gomez-Lopez N, Motomura K, Miller D, Garcia-Flores V, Galaz J & Romero R 2019a Inflammasomes: their role in normal and complicated pregnancies. Journal of Immunology 203 27572769. (https://doi.org/10.4049/jimmunol.1900901)

    • Search Google Scholar
    • Export Citation
  • Gomez-Lopez N, Romero R, Garcia-Flores V, Leng Y, Miller D, Hassan SS, Hsu CD & Panaitescu B 2019b Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes. Biology of Reproduction 100 13061318. (https://doi.org/10.1093/biolre/ioy264)

    • Search Google Scholar
    • Export Citation
  • Green ES & Arck PC 2020 Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus. Seminars in Immunopathology 42 413429. (https://doi.org/10.1007/s00281-020-00807-y)

    • Search Google Scholar
    • Export Citation
  • Hardy DB, Janowski BA, Corey DR & Mendelson CR 2006 Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression. Molecular Endocrinology 20 27242733. (https://doi.org/10.1210/me.2006-0112)

    • Search Google Scholar
    • Export Citation
  • Helmo FR, Alves EAR, Moreira RAA, Severino VO, Rocha LP, Monteiro MLGDR, Reis MAD, Etchebehere RM, Machado JR & Corrêa RRM 2018 Intrauterine infection, immune system and premature birth. Journal of Maternal-Fetal and Neonatal Medicine 31 12271233. (https://doi.org/10.1080/14767058.2017.1311318)

    • Search Google Scholar
    • Export Citation
  • Higgins RD, Saade G, Polin RA, Grobman WA, Buhimschi IA, Watterberg K, Silver RM, Raju TNK & Chorioamnionitis Workshop Participants 2016 Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of a workshop. Obstetrics and Gynecology 127 426436. (https://doi.org/10.1097/AOG.0000000000001246)

    • Search Google Scholar
    • Export Citation
  • Hua R, Pease JE, Sooranna SR, Viney JM, Nelson SM, Myatt L, Bennett PR & Johnson MR 2012 Stretch and inflammatory cytokines drive myometrial chemokine expression via NF-kappaB activation. Endocrinology 153 481491. (https://doi.org/10.1210/en.2011-1506)

    • Search Google Scholar
    • Export Citation
  • Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, Quong AA, Latz E & Scott CP et al.2010 Anti-inflammatory compounds parthenolide and Bay 11–7082 are direct inhibitors of the inflammasome. Journal of Biological Chemistry 285 97929802. (https://doi.org/10.1074/jbc.M109.082305)

    • Search Google Scholar
    • Export Citation
  • Kawai T & Akira S 2007 Signaling to NF-kappaB by toll-like receptors. Trends in Molecular Medicine 13 460469. (https://doi.org/10.1016/j.molmed.2007.09.002)

    • Search Google Scholar
    • Export Citation
  • Kelley N, Jeltema D, Duan Y & He Y 2019 The NLRP3 inflammasome:an overview of mechanisms of activation and regulation. International Journal of Molecular Sciences 20 3328. (https://doi.org/10.3390/ijms20133328)

    • Search Google Scholar
    • Export Citation
  • Lappas M 2016 RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators. Reproduction 151 411420. (https://doi.org/10.1530/REP-15-0607)

    • Search Google Scholar
    • Export Citation
  • Lei K, Georgiou EX, Chen L, Yulia A, Sooranna SR, Brosens JJ, Bennett PR & Johnson MR 2015 Progesterone and the repression of myometrial inflammation: the roles of MKP-1 and the AP-1 system. Molecular Endocrinology 29 14541467. (https://doi.org/10.1210/me.2015-1122)

    • Search Google Scholar
    • Export Citation
  • Leimert KB, Messer A, Gray T, Fang X, Chemtob S & Olson DM 2019 Maternal and fetal intrauterine tissue crosstalk promotes proinflammatory amplification and uterine transition. Biology of Reproduction 100 783797. (https://doi.org/10.1093/biolre/ioy232)

    • Search Google Scholar
    • Export Citation
  • McCarthy R, Martin-Fairey C, Sojka DK, Herzog ED, Jungheim ES, Stout MJ, Fay JC, Mahendroo M, Reese J & Herington JL et al.2018 Mouse models of preterm birth: suggested assessment and reporting guidelines. Biology of Reproduction 99 922937. (https://doi.org/10.1093/biolre/ioy109)

    • Search Google Scholar
    • Export Citation
  • Migale R, MacIntyre DA, Cacciatore S, Lee YS, Hagberg H, Herbert BR, Johnson MR, Peebles D, Waddington SN & Bennett PR 2016 Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics. BMC Medicine 14 86. (https://doi.org/10.1186/s12916-016-0632-4)

    • Search Google Scholar
    • Export Citation
  • Oeckinghaus A, Hayden MS & Ghosh S 2011 Crosstalk in NF-kappaB signaling pathways. Nature Immunology 12 695708. (https://doi.org/10.1038/ni.2065)

    • Search Google Scholar
    • Export Citation
  • Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M & Mesiano S 2015 Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Human Reproduction Update 21 155173. (https://doi.org/10.1093/humupd/dmu056)

    • Search Google Scholar
    • Export Citation
  • Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel L & Hassan S 2007 The role of inflammation and infection in preterm birth. Seminars in Reproductive Medicine 25 2139. (https://doi.org/10.1055/s-2006-956773)

    • Search Google Scholar
    • Export Citation
  • Romero R, Dey SK & Fisher SJ 2014 Preterm labor: one syndrome, many causes. Science 345 760765. (https://doi.org/10.1126/science.1251816)

  • Romero R, Xu Y, Plazyo O, Chaemsaithong P, Chaiworapongsa T, Unkel R, Than NG, Chiang PJ, Dong Z & Xu Z et al.2018 A role for the inflammasome in spontaneous labor at term. American Journal of Reproductive Immunology 79 e12440. (https://doi.org/10.1111/aji.12440)

    • Search Google Scholar
    • Export Citation
  • Shynlova O, Nedd-Roderique T, Li Y, Dorogin A & Lye SJ 2013 Myometrial immune cells contribute to term parturition, preterm labour and post-partum involution in mice. Journal of Cellular and Molecular Medicine 17 90102. (https://doi.org/10.1111/j.1582-4934.2012.01650.x)

    • Search Google Scholar
    • Export Citation
  • Shynlova O, Nadeem L, Zhang J, Dunk C & Lye S 2020 Myometrial activation: novel concepts underlying labor. Placenta 92 2836. (https://doi.org/10.1016/j.placenta.2020.02.005)

    • Search Google Scholar
    • Export Citation
  • Vannuccini S, Bocchi C, Severi FM, Challis JR & Petraglia F 2016 Endocrinology of human parturition. Annales d’Endocrinologie 77 105113. (https://doi.org/10.1016/j.ando.2016.04.025)

    • Search Google Scholar
    • Export Citation
  • Wang Z, Zhang S, Xiao Y, Zhang W, Wu S, Qin T, Yue Y, Qian W & Li L 2020 NLRP3 inflammasome and inflammatory diseases. Oxidative Medicine and Cellular Longevity 2020 4063562. (https://doi.org/10.1155/2020/4063562)

    • Search Google Scholar
    • Export Citation
  • Yang Y, Wang H, Kouadir M, Song H & Shi F 2019 Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death and Disease 10 128. (https://doi.org/10.1038/s41419-019-1413-8)

    • Search Google Scholar
    • Export Citation
  • Yeh CC, Chen CY & Wang PH 2017 Infection and preterm birth. Journal of the Chinese Medical Association 80 530531. (https://doi.org/10.1016/j.jcma.2017.02.004)

    • Search Google Scholar
    • Export Citation
  • Yellon SM, Dobyns AE, Beck HL, Kurtzman JT, Garfield RE & Kirby MA 2013 Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. PLoS ONE 8 e81340. (https://doi.org/10.1371/journal.pone.0081340)

    • Search Google Scholar
    • Export Citation
  • You X, Liu J, Xu C, Liu W, Zhu X, Li Y, Sun Q, Gu H & Ni X 2014 Corticotropin-releasing hormone (CRH) promotes inflammation in human pregnant myometrium: the evidence of CRH initiating parturition? Journal of Clinical Endocrinology and Metabolism 99 E199E208. (https://doi.org/10.1210/jc.2013-3366)

    • Search Google Scholar
    • Export Citation
  • Young A, Thomson AJ, Ledingham M, Jordan F, Greer IA & Norman JE 2002 Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biology of Reproduction 66 445449. (https://doi.org/10.1095/biolreprod66.2.445)

    • Search Google Scholar
    • Export Citation
  • Zahid A, Li B, Kombe AJK, Jin T & Tao J 2019 Pharmacological inhibitors of the NLRP3 inflammasome. Frontiers in Immunology 10 2538. (https://doi.org/10.3389/fimmu.2019.02538)

    • Search Google Scholar
    • Export Citation