Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development

Abstract

Successful pregnancy requires carefully-coordinated communications between the mother and fetus. Immune cells and cytokine signaling pathways participate as mediators of these communications to promote healthy pregnancy. At the same time, certain infections or inflammatory conditions in pregnant mothers cause severe disease and have detrimental impacts on the developing fetus. In this review, we examine evidence for the role of maternal and fetal immune responses affecting pregnancy and fetal development, both under homeostasis and following infection. We discuss immune responses that are necessary to promote healthy pregnancy and those that lead to congenital disorders and pregnancy complications, with a particular emphasis on the role of interferons and cytokines. Understanding the contributions of the immune system in pregnancy and fetal development provides important insights into the pathogenesis underlying maternal and fetal diseases and sheds insights on possible targets for therapy.

Keywords: autoimmunity; birth defect; congenital diseases; cytokines; infections; innate immunity; interferon; maternal health; placenta.

Figure 1:. Immune responses necessary for healthy pregnancy

(A) The blastocyst attaches to and invades the maternal uterine endometrium. This process is accompanied by an evolutionary conserved inflammatory response including IL-6, IL-1, and LIF. Key cell types necessary for early pregnancy, as demonstrated by mouse models, include dendritic cells, which are essential for decidualization, and macrophages, which are essential for maintenance of the corpus luteum in the ovary. NK cells directly surround the trophoblasts after implantation. (B) During development of the placenta in the first trimester, immune cells including NK cells and mast cells are necessary for uterine spiral artery remodeling, as demonstrated by mouse models. The cytokine IFN-γ is also necessary for this process in mouse models. (C) Parturition is mediated by an inflammatory response. Macrophages and neutrophils infiltrate the uterine myometrium. IL-1β is secreted and induces muscle contraction. IL6 is necessary for on-time parturition in mouse models.

Figure 2:. Antimicrobial protective mechanisms at the placenta and decidua

A) At the chorionic villi and intervillous space, syncytiotrophoblasts (SYN) constitutively express IFNλ and exosomes, which confer resistance to viruses and other known TORCH pathogens to SYNs and neighboring cells. Maternal IgG is transferred to the fetus using FcRn receptors starting at 13 weeks of gestation in humans. B) At the anchoring villi and decidua, NK cells are capable of killing virus-infected cells and are located in close proximity to potential portals of viral entry. NK cells surround extravillous trophoblasts (EVTs) and spiral arteries. Pathogen specific CD8 T cells are enriched in the human decidua. They have the potential to be cytotoxic upon ex-vivo stimulation.

Figure 3:. Pathological effects of cytokines in pregnancy

Aberrant expression of IFN-γ, IFN-β, TNF-α, IL6, IL17, and IL-1β can lead to developmental failure in multiple organ systems. (A) Exposure of embryos to IFN-γ in culture is toxic, and systemically elevated IFN-γ at the time of implantation inhibits implantation. Mouse models implicate that IFN-γ responsiveness after malaria and toxoplasma infection mediates some of the placental defects and that IFN-γ overexpression leads to abnormal brain development in mouse models. (B) Type I IFNs (including IFNα and IFNβ) mediate abnormal placental development after ZIKV infection, as demonstrated by mouse models. Humans with overexpression of type I IFNs due to interferonopathies have abnormal brain development, similar to “TORCH” infections, implicating IFNs as mediators of abnormal brain development. (C) Exposure of embryos to TNF-α can induce a block in development. TNF-α is a mediator of fetal demise in mouse models of immune stimulation (CpG, LPS, and Poly(I:C)). TNF-α injection in mice can cause neural tube defects. Intraamniotic infusion of TNF-α is sufficient to induce preterm birth in non-human primate models. (D) IL-6 (upstream of IL-17) induces abnormal brain development and behavior in mouse models of maternal immune activation. IL-6 mediates on time and preterm parturition in mouse models. (E) IL17 (downstream of IL6) induces abnormal brain development and behavior in mouse models of maternal immune activation. (F) IL-1 may induce preterm birth, as amniotic IL-1β administration is sufficient to induce preterm labor in non-human primates. Mouse models reveal that IL-1 may mediate defects associated with peripartum intrauterine inflammation including abnormal lung development associated with bronchopulmonary dysplasia and brain injury.