Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation
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Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation. / Solano, María Emilia; Kowal, Mirka Katharina; O'Rourke, Greta Eugenia; Horst, Andrea Kristina; Modest, Kathrin; Plösch, Torsten; Barikbin, Roja; Remus, Chressen Catharina; Berger, Robert G; Jago, Caitlin; Ho, Hoang; Sass, Gabriele; Parker, Victoria J; Lydon, John P; DeMayo, Francesco J; Hecher, Kurt; Karimi, Khalil; Arck, Petra Clara.
in: J CLIN INVEST, Jahrgang 125, Nr. 4, 01.04.2015, S. 1726-38.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -