Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation
María Emilia Solano, … , Khalil Karimi, Petra Clara Arck
María Emilia Solano, … , Khalil Karimi, Petra Clara Arck
Published March 16, 2015
Citation Information: J Clin Invest. 2015;125(4):1726-1738. https://doi.org/10.1172/JCI68140.
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Research Article Reproductive biology

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

Abstract

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor– or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.

Authors

María Emilia Solano, Mirka Katharina Kowal, Greta Eugenia O’Rourke, Andrea Kristina Horst, Kathrin Modest, Torsten Plösch, Roja Barikbin, Chressen Catharina Remus, Robert G. Berger, Caitlin Jago, Hoang Ho, Gabriele Sass, Victoria J. Parker, John P. Lydon, Francesco J. DeMayo, Kurt Hecher, Khalil Karimi, Petra Clara Arck

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Figure 1

Prenatal stress results in fetal-growth restriction and placental insufficiency.

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Prenatal stress results in fetal-growth restriction and placental insuff...
(A) Fetal development was scored on gd16.5 according to TS criteria. (B) Representative photograph of a TS 25 fetus on gd16.5 depicting parallel fingers and toes, fused eyelids, and thickened skin that forms wrinkles. (C) Photograph of a prenatally stress-challenged gd16.5 fetus in TS 24, exhibiting divergent toes and fingers, open eyelids, and thin skin without wrinkles. (D) Fetal weight on gd16.5, (E) gestational length, and (F) postnatal day 2 weight from control and prenatally stress-challenged litters. (G) L/Jz ratio, obtained upon histomorphometric analyses of Masson-stained placental tissue sections harvested on gd12.5 to gd16.5. (H) Fetal vessel density in the placental labyrinth, calculated as CD34+ vessel number per visual field (VF). Arrows indicate the beginning of the 24-hour exposure to sound stress. (I) Representative photomicrographs depict midsagittal sections of gd14.5 and gd16.5 placental tissue. Top panels: Masson staining allows differentiating the labyrinth and junctional zone. Bottom panels: CD34+ (red) fetal vessels in the placental labyrinth labeled by immunofluorescence; cell nuclei were counterstained with DAPI (blue). Scale bars: 1 mm (top panels); 0.1 mm (lower panels). The n used in each group and experiment is depicted inside the bars (A and D–F). For parts G and H, a minimum of 8 placentas per group and gd were quantified to identify differences between groups. (A and D–H) Data represent the mean ± SEM. *P ≤ 0.05; **P ≤ 0.001; Mann-Whitney U test (D–H) and χ2 test (A) were used to calculate the statistical differences between groups (A: χ2 (2,N = 128) = 9.357).