Regular article
Immunopathology and infectious disease
Placental TNF-α Signaling in Illness-Induced Complications of Pregnancy

https://doi.org/10.1016/j.ajpath.2011.02.042Get rights and content

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.

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Supported by grants from the March of Dimes, Autism Speaks, and the Blume Foundation (T.D.P.); by fellowship support from the Lucile Packard Foundation and NIH F32 NS060427-01A1 and NIH 5T90DK070103-04 (P.A.C.); and by fellowship support from the Howard Hughes Medical Foundation (A.L.D.).

Supplemental material for this article can be found at http://ajp.amjpathol.org or at doi: 10.1016/j.ajpath.2011.02.042.

Current address of A.L.D., Department of Pediatrics, University of Colorado, Denver, Colorado.

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