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

TY - JOUR

T1 - Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

AU - Solano, María Emilia

AU - Kowal, Mirka Katharina

AU - O'Rourke, Greta Eugenia

AU - Horst, Andrea Kristina

AU - Modest, Kathrin

AU - Plösch, Torsten

AU - Barikbin, Roja

AU - Remus, Chressen Catharina

AU - Berger, Robert G

AU - Jago, Caitlin

AU - Ho, Hoang

AU - Sass, Gabriele

AU - Parker, Victoria J

AU - Lydon, John P

AU - DeMayo, Francesco J

AU - Hecher, Kurt

AU - Karimi, Khalil

AU - Arck, Petra Clara

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

U2 - 10.1172/JCI68140

DO - 10.1172/JCI68140

M3 - SCORING: Journal article

C2 - 25774501

VL - 125

SP - 1726

EP - 1738

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 4

ER -