Maternal peripheral blood natural killer cells incorporate placenta-associated microRNAs during pregnancy

Ishida,Yoichi; Zhao,Dongwei; Ohkuchi,Akihide; Kuwata,Tomoyuki; Yoshitake,Hiroshi; Yuge,Kazuya; Takizawa,Takami; Matsubara,Shigeki; Suzuki,Mitsuaki; Saito,Shigeru; Takizawa,Toshihiro

doi:10.3892/ijmm.2015.2157

Maternal peripheral blood natural killer cells incorporate placenta-associated microRNAs during pregnancy

Authors:
- Yoichi Ishida
- Dongwei Zhao
- Akihide Ohkuchi
- Tomoyuki Kuwata
- Hiroshi Yoshitake
- Kazuya Yuge
- Takami Takizawa
- Shigeki Matsubara
- Mitsuaki Suzuki
- Shigeru Saito
- Toshihiro Takizawa
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Affiliations: Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329‑0498, Japan, Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8602, Japan, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama 930‑0194, Japan
Published online on: March 27, 2015 https://doi.org/10.3892/ijmm.2015.2157
Pages: 1511-1524
Copyright: © Ishida et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Although recent studies have demonstrated that microRNAs (miRNAs or miRs) regulate fundamental natural killer (NK) cellular processes, including cytotoxicity and cytokine production, little is known about the miRNA‑gene regulatory relationships in maternal peripheral blood NK (pNK) cells during pregnancy. In the present study, to determine the roles of miRNAs within gene regulatory networks of maternal pNK cells, we performed comprehensive miRNA and gene expression profiling of maternal pNK cells using a combination of reverse transcription quantitative PCR (RT‑qPCR)‑based miRNA array and DNA microarray analyses and analyzed the differential expression levels between first‑ and third‑trimester pNK cells. Furthermore, we constructed regulatory networks for miRNA‑mediated gene expression in pNK cells during pregnancy by Ingenuity Pathway Analysis (IPA). PCR‑based array analysis revealed that the placenta‑derived miRNAs [chromosome 19 miRNA cluster (C19MC) miRNAs] were detected in pNK cells during pregnancy. Twenty‑five miRNAs, including six C19MC miRNAs, were significantly upregulated in the third‑ compared to first‑trimester pNK cells. The rapid clearance of C19MC miRNAs also occurred in the pNK cells following delivery. Nine miRNAs, including eight C19MC miRNAs, were significantly downregulated in the post‑delivery pNK cells compared to those of the third‑trimester. DNA microarray analysis identified 69 NK cell function‑related genes that were differentially expressed between the first‑ and third‑trimester pNK cells. On pathway and network analysis, the observed gene expression changes of pNK cells likely contribute to the increase in the cytotoxicity, as well as the cell cycle progression of third‑ compared to first‑trimester pNK cells. Thirteen of the 69 NK cell function‑related genes were significantly downregulated between the first‑ and third‑trimester pNK cells. Nine of the 13 downregulated NK‑function‑associated genes were in silico target candidates of 12 upregulated miRNAs, including C19MC miRNA miR‑512‑3p. The results of this study suggest that the transfer of placental C19MC miRNAs into maternal pNK cells occurs during pregnancy. The present study provides new insight into maternal NK cell functions.

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1	Vivier E, Tomasello E, Baratin M, Walzer T and Ugolini S: Functions of natural killer cells. Nat Immunol. 9:503–510. 2008. View Article : Google Scholar : PubMed/NCBI
2	Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM and Ugolini S: Innate or adaptive immunity? The example of natural killer cells. Science. 331:44–49. 2011. View Article : Google Scholar : PubMed/NCBI
3	Carrega P and Ferlazzo G: Natural killer cell distribution and trafficking in human tissues. Front Immunol. 3:3472012. View Article : Google Scholar : PubMed/NCBI
4	Kalkunte S, Chichester CO, Gotsch F, Sentman CL, Romero R and Sharma S: Evolution of non-cytotoxic uterine natural killer cells. Am J Reprod Immunol. 59:425–432. 2008. View Article : Google Scholar : PubMed/NCBI
5	Santoni A, Carlino C, Stabile H and Gismondi A: Mechanisms underlying recruitment and accumulation of decidual NK cells in uterus during pregnancy. Am J Reprod Immunol. 59:417–424. 2008. View Article : Google Scholar : PubMed/NCBI
6	Moffett A and Colucci F: Uterine NK cells: Active regulators at the maternal-fetal interface. J Clin Invest. 124:1872–1879. 2014. View Article : Google Scholar : PubMed/NCBI
7	Hedlund M, Stenqvist AC, Nagaeva O, Kjellberg L, Wulff M, Baranov V and Mincheva-Nilsson L: Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: Evidence for immunosuppressive function. J Immunol. 183:340–351. 2009. View Article : Google Scholar : PubMed/NCBI
8	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
9	Rossi RL, Rossetti G, Wenandy L, Curti S, Ripamonti A, Bonnal RJ, Birolo RS, Moro M, Crosti MC, Gruarin P, et al: Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4⁺ T cells by the microRNA miR-125b. Nat Immunol. 12:796–803. 2011. View Article : Google Scholar : PubMed/NCBI
10	Allantaz F, Cheng DT, Bergauer T, Ravindran P, Rossier MF, Ebeling M, Badi L, Reis B, Bitter H, DAsaro M, et al: Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression. PLoS One. 7:e299792012. View Article : Google Scholar : PubMed/NCBI
11	Wang P, Gu Y, Zhang Q, Han Y, Hou J, Lin L, Wu C, Bao Y, Su X, Jiang M, et al: Identification of resting and type I IFN-activated human NK cell miRNomes reveals microRNA-378 and microRNA-30e as negative regulators of NK cell cytotoxicity. J Immunol. 189:211–221. 2012. View Article : Google Scholar : PubMed/NCBI
12	Liu X, Wang Y, Sun Q, Yan J, Huang J, Zhu S and Yu J: Identification of microRNA transcriptome involved in human natural killer cell activation. Immunol Lett. 143:208–217. 2012. View Article : Google Scholar : PubMed/NCBI
13	Kambe S, Yoshitake H, Yuge K, Ishida Y, Ali MM, Takizawa T, Kuwata T, Ohkuchi A, Matsubara S, Suzuki M, et al: Human exosomal placenta-associated miR-517a-3p modulates the expression of PRKG1 mRNA in Jurkat cells. Biol Reprod. 91:1292014. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
15	Dybkaer K, Iqbal J, Zhou G, Geng H, Xiao L, Schmitz A, d’Amore F and Chan WC: Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: Gene expression signatures indicative of novel molecular signaling pathways. BMC Genomics. 8:2302007. View Article : Google Scholar : PubMed/NCBI
16	Morales-Prieto DM, Ospina-Prieto S, Schmidt A, Chaiwangyen W and Markert UR: Elsevier Trophoblast Research Award Lecture: Origin, evolution and future of placenta miRNAs. Placenta. 35(Suppl): pp. S39–S45. 2014, View Article : Google Scholar
17	Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, et al: Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 37:766–770. 2005. View Article : Google Scholar : PubMed/NCBI
18	Noguer-Dance M, Abu-Amero S, Al-Khtib M, Lefèvre A, Coullin P, Moore GE and Cavaillé J: The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta. Hum Mol Genet. 19:3566–3582. 2010. View Article : Google Scholar : PubMed/NCBI
19	Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, Takizawa T, Shigihara T, Goto T, Izumi A, et al: Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod. 81:717–729. 2009. View Article : Google Scholar : PubMed/NCBI
20	Taylor DD, Akyol S and Gercel-Taylor C: Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol. 176:1534–1542. 2006. View Article : Google Scholar : PubMed/NCBI
21	Doisneau-Sixou SF, Sergio CM, Carroll JS, Hui R, Musgrove EA and Sutherland RL: Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr Relat Cancer. 10:179–186. 2003. View Article : Google Scholar : PubMed/NCBI
22	Curran EM, Berghaus LJ, Vernetti NJ, Saporita AJ, Lubahn DB and Estes DM: Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway. Cell Immunol. 214:12–20. 2001. View Article : Google Scholar
23	van den Heuvel MJ, Xie X, Tayade C, Peralta C, Fang Y, Leonard S, Paffaro VA Jr, Sheikhi AK, Murrant C and Croy BA: A review of trafficking and activation of uterine natural killer cells. Am J Reprod Immunol. 54:322–331. 2005. View Article : Google Scholar : PubMed/NCBI
24	Yusa S, Catina TL and Campbell KS: SHP-1- and phosphotyrosine-independent inhibitory signaling by a killer cell Ig-like receptor cytoplasmic domain in human NK cells. J Immunol. 168:5047–5057. 2002. View Article : Google Scholar : PubMed/NCBI
25	Lu SX, Kappel LW, Charbonneau-Allard AM, Atallah R, Holland AM, Turbide C, Hubbard VM, Rotolo JA, Smith M, Suh D, et al: Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation. PLoS One. 6:e216112011. View Article : Google Scholar : PubMed/NCBI
26	Van Kaer L: Regulation of immune responses by CD1d-restricted natural killer T cells. Immunol Res. 30:139–153. 2004. View Article : Google Scholar : PubMed/NCBI
27	Ueda N, Kuki H, Kamimura D, Sawa S, Seino K, Tashiro T, Fushuku K, Taniguchi M, Hirano T and Murakami M: CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8⁺ T cells in a manner dependent on IL-4. Int Immunol. 18:1397–1404. 2006. View Article : Google Scholar : PubMed/NCBI
28	Li D, Wang L, Yu L, Freundt EC, Jin B, Screaton GR and Xu XN: Ig-like transcript 4 inhibits lipid antigen presentation through direct CD1d interaction. J Immunol. 182:1033–1040. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ujike A, Takeda K, Nakamura A, Ebihara S, Akiyama K and Takai T: Impaired dendritic cell maturation and increased T(H)2 responses in PIR-B(−/−) mice. Nat Immunol. 3:542–548. 2002. View Article : Google Scholar : PubMed/NCBI
30	Cooper MA, Fehniger TA and Caligiuri MA: The biology of human natural killer-cell subsets. Trends Immunol. 22:633–640. 2001. View Article : Google Scholar : PubMed/NCBI
31	Jabrane-Ferrat N and Siewiera J: The up side of decidual natural killer cells: New developments in immunology of pregnancy. Immunology. 141:490–497. 2014. View Article : Google Scholar :
32	Joncker NT, Shifrin N, Delebecque F and Raulet DH: Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J Exp Med. 207:2065–2072. 2010. View Article : Google Scholar : PubMed/NCBI
33	Elliott JM, Wahle JA and Yokoyama WM: MHC class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J Exp Med. 207:2073–2079. 2010. View Article : Google Scholar : PubMed/NCBI
34	Beaulieu AM, Bezman NA, Lee JE, Matloubian M, Sun JC and Lanier LL: MicroRNA function in NK-cell biology. Immunol Rev. 253:40–52. 2013. View Article : Google Scholar : PubMed/NCBI
35	Leong JW, Sullivan RP and Fehniger TA: microRNA management of NK developmental and functional programs. Eur J Immunol. 44:2862–2868. 2014. View Article : Google Scholar : PubMed/NCBI