Placental TNF-α signaling in illness-induced complications of pregnancy

Am J Pathol. 2011 Jun;178(6):2802-10. doi: 10.1016/j.ajpath.2011.02.042.

Abstract

Maternal infections are implicated in a variety of complications during pregnancy, including pregnancy loss, prematurity, and increased risk of neurodevelopmental disorders in the child. Here, we show in mice that even mild innate immune activation by low-dose lipopolysaccharide in early pregnancy causes hemorrhages in the placenta and increases the risk of pregnancy loss. Surviving fetuses exhibit hypoxia in the brain and impaired fetal neurogenesis. Maternal Toll-like receptor 4 signaling is a critical mediator of this process, and its activation is accompanied by elevated proinflammatory cytokines in the placenta. We evaluated the role of tumor necrosis factor-α (TNF-α) signaling and show that TNF receptor 1 (TNFR1) is necessary for the illness-induced placental pathology, accompanying fetal hypoxia, and neuroproliferative defects in the fetal brain. We also show that placental TNFR1 in the absence of maternal TNFR1 is sufficient for placental pathology to develop and that a clinically relevant TNF-α antagonist prevents placental pathology and fetal loss. Our observations suggest that the placenta is highly sensitive to proinflammatory signaling in early pregnancy and that TNF-α is an effective target for preventing illness-related placental defects and related risks to the fetus and fetal brain development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Proliferation / drug effects
  • Cytokines / blood
  • Embryo Loss / immunology
  • Embryo Loss / pathology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / immunology
  • Female
  • Fetus / blood supply
  • Fetus / drug effects
  • Fetus / metabolism
  • Fetus / pathology
  • Immunity / drug effects
  • Lipopolysaccharides / pharmacology
  • Mice
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neurogenesis / drug effects
  • Oxygen / metabolism
  • Placenta / drug effects
  • Placenta / immunology
  • Placenta / metabolism*
  • Placenta / pathology
  • Pregnancy
  • Pregnancy Complications / immunology
  • Pregnancy Complications / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction* / drug effects
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Cytokines
  • Lipopolysaccharides
  • Receptors, Tumor Necrosis Factor, Type I
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Oxygen