To investigate CXC chemokine receptor 2 (CXCR2)-mediated granulocytic myeloid-derived suppressor cells' (MDSCs) (G-MDSCs) functional characterization and their role in maternal–fetal interface. Proportions of CXCR2+ MDSCs and CXCR2 protein levels in total MDSCs were lower in abortion-prone CBA/J×DBA/2 mice than in CBA/J×BALB/c mice with normal pregnancy. Treatment with CXCR2 neutralizing antibody in vivo at early stage of pregnancy significantly increased the embryo resorption rates and reduced MDSCs abundance in mice from CBA/J×BALB/c matings. Adoptive transfer of MDSCs improved pregnancy outcomes in anti-CXCR2-pretreated CBA/J mice in CBA/J×BALB/C matings. CXCR2 was capable of enhancing the migration of G-MDSCs efficiently instead of monocytic MDSCs (M-MDSCs). In addition to preferential G-MDSC accumulation, arginase I expression as well as arginase I activity of G-MDSCs were regulated by CXCR2. CXCL1, as one of CXCR2 ligands, correlated well with CXCR2-mediated G-MDSCs migration and arginase I activity. CXCR2/CXCL1 axis promotes G-MDSC recruitment and facilitates arginase I expression and activity of these cells at maternal–fetal interface. These findings provide comprehensive insights into how G-MDSCs are recruited to decidual tissues and how local G-MDSCs maintain pregnancy tolerance.
Get full access to this article
View all access options for this article.
References
1.
AgaugueS., CarosellaE.D., and Rouas-FreissN. (2011). Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17. Blood, 117, 7021–7031.
2.
ArckP.C., and HecherK. (2013). Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. Nat Med, 19, 548–556.
3.
BradleyM.E., DombrechtB., ManiniJ., WillisJ., VlerickD., De TaeyeS., et al. (2015). Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action. Mol Pharmacol, 87, 251–262.
4.
BronteV., and ZanovelloP. (2005). Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol, 5, 641–654.
5.
ClarkD.A., ChaouatG., ArckP.C., MittrueckerH.W., and LevyG.A. (1998). Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase [correction of prothombinase]. J Immunol, 160, 545–549.
6.
CorralizaI.M., CampoM.L., SolerG., and ModolellM. (1994). Determination of arginase activity in macrophages: a micromethod. J Immunol Methods, 174, 231–235.
7.
DelanoM.J., ScumpiaP.O., WeinsteinJ.S., CocoD., NagarajS., Kelly-ScumpiaK.M., et al. (2007). MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med, 204, 1463–1474.
8.
DuM.R., WangS.C., and LiD.J. (2014). The integrative roles of chemokines at the maternal-fetal interface in early pregnancy. Cell Mol Immunol, 11, 438–448.
9.
FilipazziP., ValentiR., HuberV., PillaL., CaneseP., IeroM., et al. (2007). Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol, 25, 2546–2553.
10.
GabrilovichD.I., and NagarajS. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol, 9, 162–174.
11.
GabrilovichD.I., BronteV., ChenS.H., ColomboM.P., OchoaA., Ostrand-RosenbergS., et al. (2007). The terminology issue for myeloid-derived suppressor cells. Cancer research, 67, 425; author reply 6.
12.
GellersenB., BrosensI.A., and BrosensJ.J. (2007). Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med, 25, 445–453.
13.
GoniO., AlcaideP., and FresnoM. (2002). Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+))CD11b(+) immature myeloid suppressor cells. Int Immunol, 14, 1125–1134.
14.
HammondM.E., ShyamalaV., SianiM.A., GallegosC.A., FeuchtP.H., AbbottJ., et al. (1996). Receptor recognition and specificity of interleukin-8 is determined by residues that cluster near a surface-accessible hydrophobic pocket. J Biol Chem, 271, 8228–8235.
15.
HargerJ.H., ArcherD.F., MarcheseS.G., Muracca-ClemensM., and GarverK.L. (1983). Etiology of recurrent pregnancy losses and outcome of subsequent pregnancies. Obstet Gynecol, 62, 574–581.
16.
KatohH., WangD., DaikokuT., SunH., DeyS.K., and DuboisR.N. (2013). CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell, 24, 631–644.
17.
KigerN., ChaouatG., KolbJ.P., WegmannT.G., and GuenetJ.L. (1985). Immunogenetic studies of spontaneous abortion in mice. Preimmunization of females with allogeneic cells. J Immunol, 134, 2966–2970.
18.
KostlinN., KugelH., SpringB., LeiberA., MarmeA., HenesM., et al. (2014). Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T-cell responses. Eur J Immunol, 44, 2582–2591.
19.
KropfP., BaudD., MarshallS.E., MunderM., MosleyA., FuentesJ.M., et al. (2007). Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy. Eur J Immunol, 37, 935–945.
20.
MakarenkovaV.P., BansalV., MattaB.M., PerezL.A., and OchoaJ.B. (2006). CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol, 176, 2085–2094.
21.
MarigoI., DolcettiL., SerafiniP., ZanovelloP., and BronteV. (2008). Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev, 222, 162–179.
22.
MautiL.A., Le BitouxM.A., BaumerK., StehleJ.C., GolshayanD., ProveroP., et al. (2011). Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation. J Clin Invest, 121, 2794–2807.
23.
McCordN., AyukP., McMahonM., BoydR.C., SargentI., and RedmanC. (2006). System y+ arginine transport and NO production in peripheral blood mononuclear cells in pregnancy and preeclampsia. Hypertension, 47, 109–115.
24.
MovahediK., GuilliamsM., Van den BosscheJ., Van den BerghR., GysemansC., BeschinA., et al. (2008). Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood, 111, 4233–4244.
25.
NairR.R., SinhaP., KhannaA., and SinghK. (2015). Reduced myeloid-derived suppressor cells in the blood and endometrium is associated with early miscarriage. Am J Reprod Immunol, 73, 479–486.
26.
NauschN., GalaniI.E., SchleckerE., and CerwenkaA. (2008). Mononuclear myeloid-derived “suppressor” cells express RAE-1 and activate natural killer cells. Blood, 112, 4080–4089.
27.
ObermajerN., WongJ.L., EdwardsR.P., OdunsiK., MoysichK., and KalinskiP. (2012). PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol Invest, 41, 635–657.
28.
PitmanH., InnesB.A., RobsonS.C., BulmerJ.N., and LashG.E. (2013). Altered expression of interleukin-6, interleukin-8 and their receptors in decidua of women with sporadic miscarriage. Hum Reprod, 28, 2075–2086.
29.
ShahineL., and LathiR. (2015). Recurrent pregnancy loss: evaluation and treatment. Obstetrics Gynecol Clinics North Am, 42, 117–134.
30.
SinhaP., ClementsV.K., FultonA.M., and Ostrand-RosenbergS. (2007). Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res, 67, 4507–4513.
31.
Stray-PedersenB., and Stray-PedersenS. (1984). Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol, 148, 140–146.
32.
SunY., QinX., ShanB., WangW., ZhuQ., SharmaS., et al. (2013). Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls. Fertil Steril, 99, 1759–1767.
33.
ThaxtonJ.E., RomeroR., and SharmaS. (2009). TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes. J Immunol, 183, 1144–1154.
34.
TomettenM., BloisS., KuhlmeiA., StretzA., KlappB.F., and ArckP.C. (2006). Nerve growth factor translates stress response and subsequent murine abortion via adhesion molecule-dependent pathways. Biol Reprod, 74, 674–683.
35.
Vadillo-OrtegaF., Perichart-PereraO., EspinoS., Avila-VergaraM.A., IbarraI., AhuedR., et al. (2011). Effect of supplementation during pregnancy with l-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ, 342, d2901.
36.
YinG., LiC., ShanB., WangW., ChenH., ZhongY., et al. (2011). Insufficient peroxiredoxin-2 expression in uterine NK cells obtained from a murine model of abortion. J Cell Biochem, 112, 773–781.
37.
ZhuB., BandoY., XiaoS., YangK., AndersonA.C., KuchrooV.K., et al. (2007). CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. J Immunol, 179, 5228–5237.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
