title: Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice.
abstract: Maternal immune cells are an integral part of reproduction, but how they might cause pregnancy complications remains elusive. Macrophages and their dual function in inflammation and tissue repair are thought to play key yet undefined roles. Altered perinatal growth underpins adult morbidity, and natural killer (NK) cells may sustain fetal growth by establishing the placental blood supply. Using a mouse model of genetic inactivation of PI3K p110δ, a key intracellular signaling molecule in leukocytes, we show that p110δ regulates macrophage dynamics and NK-cell-mediated arterial remodeling. The uterus of dams with inactive p110δ had decreased IFN-γ and MHC class II(low) macrophages but enhanced IL-6. Poor vascular remodeling and a pro-inflammatory uterine milieu resulted in fetal death or growth retardation. Our results provide one mechanism that explains how imbalanced adaptations of maternal innate immune cells to gestation affect offspring well-being with consequence perinatally and possibly into adulthood.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Box 111, Hills Road, Cambridge CB2 0SP, UK; Centre for Trophoblast Research, University of Cambridge, Physiology Building, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Jens
authors.initials: J
authors.lastname: Kieckbusch
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Box 111, Hills Road, Cambridge CB2 0SP, UK; Centre for Trophoblast Research, University of Cambridge, Physiology Building, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Balmas
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Box 111, Hills Road, Cambridge CB2 0SP, UK.
authors.forename: Delia A
authors.initials: DA
authors.lastname: Hawkes
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Box 111, Hills Road, Cambridge CB2 0SP, UK; Centre for Trophoblast Research, University of Cambridge, Physiology Building, Downing Street, Cambridge CB2 3EG, UK. Electronic address: fc287@medschl.cam.ac.uk.
authors.forename: Francesco
authors.initials: F
authors.lastname: Colucci
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation / Q000201:enzymology / Q000276:immunology; D020868:Gene Silencing; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction; D014599:Uterus / Q000276:immunology
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse