Interleukin-34 is present at the fetal-maternal interface and induces immunoregulatory macrophages of a decidual phenotype in vitro

R. Lindau, R. B. Mehta, G. E. Lash, G. Papapavlou, R. Boij, G. Berg, M. C. Jenmalm, J. Ernerudh, J. Svensson-Arvelund

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39 Scopus citations

Abstract

STUDY QUESTION: Is the newly discovered cytokine interleukin (IL)-34 expressed at the human fetalmaternal interface in order to influence polarization of monocytes into macrophages of a decidual immunoregulatory phenotype? SUMMARY ANSWER: IL-34 was found to be present at the fetalmaternal interface, in both fetal placenta and maternal decidua, and it was able to polarize monocytes into macrophages of a decidual phenotype. WHAT IS KNOWN ALREADY: IL-34 was shown to bind to the same receptor as macrophage-colony stimulating factor (M-CSF), which has an important immunomodulatory role at the fetalmaternal interface, for example by polarizing decidual macrophages to an M2-like regulatory phenotype. IL-34 is known to regulate macrophage subsets, such as microglia and Langerhans cells, but its presence at the fetalmaternal interface is unknown. STUDY DESIGN, SIZE, DURATION: The presence of IL-34 at the fetalmaternal interface was evaluated by immunohistochemistry (IHC) and ELISA in placental and decidual tissues as well as in isolated trophoblast cells and decidual stromal cells obtained from first trimester elective surgical terminations of pregnancy (n = 49). IL-34 expression was also assessed in third trimester placental biopsies from women with (n = 21) or without (n = 15) pre-eclampsia. The effect of IL-34 on macrophage polarization was evaluated in an in vitro model of blood monocytes obtained from healthy volunteers (n = 14). In this model, granulocyte macrophage-colony stimulating factor (GM-CSF) serves as a growth factor for M1-like polarization, and M-CSF as a growth factor for M2-like polarization. PARTICIPANTS/MATERIALS, SETTING, METHODS: First trimester placental and decidual tissues were obtained from elective pregnancy terminations. Placental biopsies were obtained from women with pre-eclampsia and matched controls in the delivery ward. Polarization of macrophages in vitro was determined by flow-cytometric phenotyping and secretion of cytokines and chemokines in cell-free supernatants by multiplex bead assay. MAIN RESULTS AND THE ROLE OF CHANCE: Our study shows that IL-34 is produced at the fetalmaternal interface by both placental cyto-and syncytiotrophoblasts and decidual stromal cells. We also show that IL-34, in vitro, is able to polarize blood monocytes into macrophages with a phenotype (CD14highCD163+CD209+) and cytokine secretion pattern similar to that of decidual macrophages. The IL-34-induced phenotype was similar, but not identical to the phenotype induced by M-CSF, and both IL-34-and M-CSF-induced macrophages were significantly different (P < 0.050.0001 depending on marker) from GM-CSF-polarized M1-like macrophages. Our findings suggest that IL-34 is involved in the establishment of the tolerant milieu found at the fetalmaternal interface by skewing polarization of macrophages into a regulatory phenotype. LIMITATIONS, REASONS FOR CAUTION: Although it is clear that IL-34 is present at the fetalmaternal interface and polarizes macrophages in vitro, its precise role in vivo remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The recently discovered cytokine IL-34 is present at the fetalmaternal interface and has immunomodulatory properties with regard to induction of decidual macrophages, which are important for a healthy pregnancy. Knowledge of growth factors related to macrophage polarization can potentially be translated to treatment of pregnancy complications involving dysregulation of this process.

Original languageEnglish
Pages (from-to)588-599
Number of pages12
JournalHuman Reproduction
Volume33
Issue number4
DOIs
StatePublished - 1 Apr 2018
Externally publishedYes

Keywords

  • Interleukin-34
  • decidua
  • fetalmaternal interface
  • macrophage
  • placenta
  • pregnancy
  • tolerance

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