title: 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.forename: María Emilia
authors.initials: ME
authors.lastname: Solano
authors.forename: Mirka Katharina
authors.initials: MK
authors.lastname: Kowal
authors.forename: Greta Eugenia
authors.initials: GE
authors.lastname: O'Rourke
authors.forename: Andrea Kristina
authors.initials: AK
authors.lastname: Horst
authors.forename: Kathrin
authors.initials: K
authors.lastname: Modest
authors.forename: Torsten
authors.initials: T
authors.lastname: Plösch
authors.forename: Roja
authors.initials: R
authors.lastname: Barikbin
authors.forename: Chressen Catharina
authors.initials: CC
authors.lastname: Remus
authors.forename: Robert G
authors.initials: RG
authors.lastname: Berger
authors.forename: Caitlin
authors.initials: C
authors.lastname: Jago
authors.forename: Hoang
authors.initials: H
authors.lastname: Ho
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Parker
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: Kurt
authors.initials: K
authors.lastname: Hecher
authors.forename: Khalil
authors.initials: K
authors.lastname: Karimi
authors.forename: Petra Clara
authors.initials: PC
authors.lastname: Arck
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019175:DNA Methylation; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D005317:Fetal Growth Retardation / Q000276:immunology / Q000517:prevention & control*; D005333:Fetus / Q000276:immunology / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009622:Noise / Q000009:adverse effects; D010920:Placenta / Q000276:immunology* / Q000378:metabolism; D021041:Placental Circulation; D010927:Placental Insufficiency / Q000209:etiology / Q000276:immunology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics / Q000276:immunology* / Q000523:psychology; D011374:Progesterone / Q000096:biosynthesis / Q000502:physiology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013315:Stress, Psychological / Q000235:genetics / Q000276:immunology*
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D011374:Progesterone; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse