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Journal of Assisted Reproduction and Genetics

Erschienen in:

30.07.2022 | Reproductive Physiology and Disease

Prevention of intrauterine fetal growth restriction by administrating C1q/TNF-related protein 6, a specific inhibitor of the alternative complement pathway

verfasst von: Mayu Kurokawa, Ai Takeshita, Shu Hashimoto, Masayasu Koyama, Yoshiharu Morimoto, Daisuke Tachibana

Erschienen in: Journal of Assisted Reproduction and Genetics | Ausgabe 9/2022

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Abstract

Purpose

The latest treatments do not sufficiently prevent miscarriage and fetal growth restriction (FGR) in pregnant women. Here, we assessed the effects of a human protein, CTRP6, that specifically inhibits the activation of the alternative complement pathway on miscarriage, fetal and placental development.

Methods

Pregnant CBA/J mice mated with DBA/2 male mice as a model of spontaneous abortion and FGR were randomly divided into the control and CTRP6 groups. In the CTRP6 group, the mice were intravenously administered CTRP6 on days 4.5 and 6.5 post-conception (dpc). The abortion rate and fetal and placental weights on 14.5 dpc were examined. Remodeling of the spiral artery was also assessed.

Results

The abortion rate in the CTRP6 group (13%) was reduced compared to the control group (21%), but there was no statistical difference. The placental and fetal weights in the CTRP6 group were also heavier than those in the control (P < 0.05). Moreover, the thickness of the blood vessel wall in the CTRP6 group was significantly thinner than that in the control (P < 0.05) and comparable to that in the non-abortion model (CBA/J x BALB). The ratio of the inner-per-the-outer diameter of the spiral artery increased more in the CTRP6 group than that in the control (P < 0.05). As well, the Th1/Th2 cytokine ratio was significantly reduced by CTRP6 treatment.

Conclusions

Taken together, the supplementation with a protein that regulates the alternative complement pathway in vivo improves FGR and promotes spiral artery remodeling in a mouse model of miscarriage and FGR.

Nur mit Berechtigung zugänglich

Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod. 2012;27:2297–303.PubMedCrossRef

Munné S, Kaplan B, Frattarelli JL, Child T, Nakhuda G, Shamma FN, Silverberg K, Kalista T, Handyside AH, Katz-Jaffe M, Wells D, Gordon T, Stock-Myer S, Willman S, STAR Study Group. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertil Steril. 2019;112:1071–9.PubMedCrossRef

Sato T, Sugiura-Ogasawara M, Ozawa F, Yamamoto T, Kato T, Kurahashi H, Kuroda T, Aoyama N, Kato K, Kobayashi R, Fukuda A, Utsunomiya T, Kuwahara A, Saito H, Takeshita T, Irahara M. Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure. Hum Reprod. 2019;34:2340–428.PubMedCrossRef

Le Bouteiller P, Bensussan A. Up-and-down immunity of pregnancy in humans. F1000Res. 2017;6:1216.PubMedPubMedCentralCrossRef

Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990;248:220–3.PubMedCrossRef

Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.PubMedCrossRef

Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7:241–6.PubMedCrossRef

Moffett A, Colucci F. Uterine NK-cells: active regulators at the maternal-fetal interface. J Clin Invest. 2014;124:1872–9.PubMedPubMedCentralCrossRef

El Costa H, Tabiasco J, Berrebi A, Parant O, Aguerre-Girr M, Piccinni MP, Le Bouteiller P. Effector functions of human decidual NK cells in healthy early pregnancy are dependent on the specific engagement of natural cytotoxicity receptors. J Reprod Immunol. 2009;82:142–7.PubMedCrossRef

10.

Yang F, Zheng Q, Jin L. Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface. Front Immunol. 2019;10:2317.PubMedPubMedCentralCrossRef

11.

Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J. T Helper (Th) Cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells. Front Immunol. 2020;11:2025.PubMedPubMedCentralCrossRef

12.

Lin Y, Ren L, Wang W, Di J, Zeng S, Saito S. Effect of TLR3 and TLR7 activation in uterine NK cells from non-obese diabetic (NOD) mice. J Reprod Immunol. 2009;82:12–3.PubMedCrossRef

13.

Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006;203:2165–75.PubMedPubMedCentralCrossRef

14.

Goldman AS, Prabhakar BS. The complement system. in: Baron’s Medical Microbiology (Baron S et al, eds.) (4th ed. ed.). Univ of Texas Medical Branch. 1996

15.

Girardi G, Prohászka Z, Bulla R, Tedesco F, Scherjon S. Complement activation in animal and human pregnancies as a model for immunological recognition. Mol Immunol. 2011;48:1621–30.PubMedCrossRef

16.

van de Geijn FE, Dolhain RJ, van Rijs W, Hazes JM, de Groot CJ. Mannose-binding lectin genotypes and pre-eclampsia: a case-control study. Hum Immunol. 2007;68:888–93.PubMedCrossRef

17.

Than NG, Romero R, Erez O, Kusanovic JP, Tarca AL, Edwin SS, Kim JS, Hassan SS, Espinoza J, Mittal P, Mazaki-Tovi S, Friel L, Gotsch F, Vaisbuch E, Camacho N, Papp Z. A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia. Am J Reprod Immunol. 2008;60:333–45.PubMedPubMedCentralCrossRef

18.

Vianna P, Da Silva GK, Dos Santos BP, Bauer ME, Dalmáz CA, Bandinelli E, Chies JA. Association between mannose-binding lectin gene polymorphisms and pre-eclampsia in Brazilian women. Am J Reprod Immunol. 2010;64:359–74.PubMed

19.

Glotov AS, Tiys ES, Vashukova ES, Pakin VS, Demenkov PS, Saik OV, Ivanisenko TV, Arzhanova ON, Mozgovaya EV, Zainulina MS, Kolchanov NA, Baranov VS, Ivanisenko VA. Molecular association of pathogenetic contributors to pre-eclampsia (pre-eclampsia associome). BMC Syst Biol. 2015;9:S4.PubMedPubMedCentralCrossRef

20.

Wu W, Yang H, Feng Y, Zhang P, Li S, Wang X, Peng T, Wang F, Xie B, Guo P, Li M, Wang Y, Zhao N, Wang D, Wang S, Zhang Y. Polymorphisms in complement genes and risk of preeclampsia in Taiyuan. China Inflamm Res. 2016;65:837–45.PubMedCrossRef

21.

Poveda NE, Garcés MF, Ruiz-Linares CE, Varón D, Valderrama S, Sanchez E, Castiblanco-Cortes A, Agudelo-Zapata Y, Sandoval-Alzate HF, Leal LG, Ángel-Müller E, Ruíz-Parra AI, González-Clavijo AM, Diéguez C, Nogueiras R, Caminos JE. Serum adipsin levels throughout normal pregnancy and preeclampsia. Sci Rep. 2016;6:20073.PubMedPubMedCentralCrossRef

22.

Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Revett T, Gimeno R, Lodish HF. Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem J. 2008;416:161–77.PubMedCrossRef

23.

Murayama MA, Kakuta S, Inoue A, Umeda N, Yonezawa T, Maruhashi T, Tateishi K, Ishigame H, Yabe R, Ikeda S, Seno A, Chi HH, Hashiguchi Y, Kurata R, Tada T, Kubo S, Sato N, Liu Y, Hattori M, Saijo S, Matsushita M, Fujita T, Sumida T, Iwakura Y. CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. Nat Commun. 2015;6:8483.PubMedCrossRef

24.

Sadeghi A, Fadaei R, Moradi N, Fouani FZ, Roozbehkia M, Zandieh Z, Ansaripour S, Vatannejad A, Doustimotlagh AH. Circulating levels of C1q/TNF-α-related protein 6 (CTRP6) in polycystic ovary syndrome. IUBMB Life. 2020;72:1449–59.PubMedCrossRef

25.

Tuteja G, Cheng E, Papadakis H, Bejerano G. A comprehensive database of SNPs studied in association with pre-eclampsia. Placenta. 2012;33:1055–7.PubMedCrossRef

26.

Clark DA, Chaouat G, Arck PC, Mittruecker HW, Levy GA. Cytokine-dependent abortion in CBA × DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase [correction of prothombinase]. J Immunol. 1998;160:545–9.PubMed

27.

Girardi G. Guilty as charged: all available evidence implicates complement’s role in fetal demise. Am J Reprod Immunol. 2008;59:183–92.PubMedCrossRef

28.

McKelvey K, Yenson V, Ashton A, Morris JM, McCracken SA. Embryonic/fetal mortality and intrauterine growth restriction is not exclusive to the CBA/J sub-strain in the CBA × DBA model. Sci Rep. 2016;6:35138.PubMedPubMedCentralCrossRef

29.

Takeshita A, Kusakabe KT, Hiyama M, Kuniyoshi N, Kondo T, Kano K, Kiso Y, Okada T. Dynamics and reproductive effects of complement factors in the spontaneous abortion model of CBA/J×DBA/2 mice. Immunobiology. 2014;219:385–91.PubMedCrossRef

30.

Schumacher A, Sharkey DJ, Robertson SA, Zenclussen AC. Immune cells at the fetomaternal interface: how the microenvironment modulates immune cells to hoster fetal development. J Immunol. 2018;201:325–34.PubMedCrossRef

31.

Fraser R, Whitley GS, Johnstone AP, Host AJ, Sebire NJ, Thilaganathan B, Cartwright JE. Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance. J Pathol. 2012;228:322–32.PubMedPubMedCentralCrossRef

32.

Charalambous F, Elia A, Georgiades P. Decidual spiral artery remodeling during early post-implantation period in mice: investigation of associations with decidual uNK cells and invasive trophoblast. Biochem Biophys Res Commun. 2012;417:847–52.PubMedCrossRef

33.

Staff AC. The two-stage placental model of preeclampsia: an update. J Reprod Immunol. 2019;134–5:1–10.CrossRef

34.

Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res. 2019;124:1094–112.PubMedCrossRef

35.

Sugiura-Ogasawara M, Nozawa K, Nakanishi T, Hattori Y, Ozaki Y. Complement as a predictor of further miscarriage in couples with recurrent miscarriages. Hum Reprod. 2006;21:2711–4.PubMedCrossRef

36.

Xu C, Mao D, Holers VM, Palanca B, Cheng AM, Molina H. A critical role for murine complement regulator crry in fetomaternal tolerance. Science. 2000;287:498–501.PubMedCrossRef

37.

Cunningham DS, Tichenor JR. Decay-accelerating factor protects human trophoblast from complement-mediated attack. Clin Immunol Immunopathol. 1995;74:156–61.PubMedCrossRef

38.

Girardi G. Complement activation, a threat to pregnancy. Semin Immunopathol. 2018;40:103–11.PubMedCrossRef

39.

Brooks JP, Radojicic C, Riedl MA, Newcomer SD, Banerji A, Hsu FI. Experience with intravenous plasma-derived C1-inhibitor in pregnant women with hereditary angioedema: a systematic literature review. J Allergy Clin Immunol Pract. 2020;8:1875–80.PubMedCrossRef

40.

Sarno L, Tufano A, Maruotti GM, Martinelli P, Balletta MM, Russo D. Eculizumab in pregnancy: a narrative overview. J Nephrol. 2019;32:17–25.PubMedCrossRef

41.

Höchsmann B, Murakami Y, Osato M, Knaus A, Kawamoto M, Inoue N, Hirata T, Murata S, Anliker M, Eggermann T, Jäger M, Floettmann R, Höllein A, Murase S, Ueda Y, Nishimura JI, Kanakura Y, Kohara N, Schrezenmeier H, Krawitz PM, Kinoshita T. Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation. J Clin Invest. 2019;129:5123–36.PubMedPubMedCentralCrossRef

42.

Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–4.PubMedCrossRef

43.

Nakagawa K, Kwak-Kim J, Kuroda K, Sugiyama R, Yamaguchi K. Immunosuppressive treatment using tacrolimus promotes pregnancy outcome in infertile women with repeated implantation failures. Am J Reprod Immunol. 2017 Sep;78(3):e12682.CrossRef

44.

Nakagawa K, Kwan-Kim J, Ota K, Kuroda K, Hisano M, Sugiyama R, Yamaguchi K. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015;7:353–61.CrossRef

Titel: Prevention of intrauterine fetal growth restriction by administrating C1q/TNF-related protein 6, a specific inhibitor of the alternative complement pathway
verfasst von: Mayu Kurokawa
Ai Takeshita
Shu Hashimoto
Masayasu Koyama
Yoshiharu Morimoto
Daisuke Tachibana
Publikationsdatum: 30.07.2022
Verlag: Springer US
Erschienen in: Journal of Assisted Reproduction and Genetics / Ausgabe 9/2022
Print ISSN: 1058-0468
Elektronische ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-022-02582-1

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Prevention of intrauterine fetal growth restriction by administrating C1q/TNF-related protein 6, a specific inhibitor of the alternative complement pathway