title: Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone.
abstract: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of α-galactosylceramide (α-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent α-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of α-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator-activated receptor (PPAR)γ activation, through rosiglitazone treatment, reduced the rate of α-GalCer-induced late PTB and improved neonatal survival. Administration of α-GalCer in the third trimester suppressed PPARγ activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of α-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of α-GalCer also upregulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPARγ pathway has potential as a target for prevention of this syndrome.
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Derek
authors.initials: D
authors.lastname: St Louis
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI 48825; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201;
authors.forename: Roberto
authors.identifier: http://orcid.org/0000-0002-4448-5121
authors.initials: R
authors.lastname: Romero
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Olesya
authors.initials: O
authors.lastname: Plazyo
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Marcia
authors.identifier: http://orcid.org/0000-0002-1178-6112
authors.initials: M
authors.lastname: Arenas-Hernandez
authors.affiliation: Department of Pediatrics, Neonatology Division, Wayne State University School of Medicine, Detroit, MI 48201;
authors.forename: Bogdan
authors.initials: B
authors.lastname: Panaitescu
authors.affiliation: Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201;
authors.forename: Tatjana
authors.identifier: http://orcid.org/0000-0001-5917-9912
authors.initials: T
authors.lastname: Milovic
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatti
authors.affiliation: Immunology Program, Henry Ford Health System, Detroit, MI 48202; Department of Dermatology, Henry Ford Health System, Detroit, MI 48202; and Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201.
authors.forename: Qing-Sheng
authors.identifier: http://orcid.org/0000-0002-1411-6827
authors.initials: QS
authors.lastname: Mi
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201;
authors.forename: Sascha
authors.initials: S
authors.lastname: Drewlo
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Adi L
authors.identifier: http://orcid.org/0000-0002-9281-126X
authors.initials: AL
authors.lastname: Tarca
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201; Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/U.S. Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201; Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201 nardhy.gomez-lopez@wayne.edu ngomezlo@med.wayne.edu.
authors.forename: Nardhy
authors.initials: N
authors.lastname: Gomez-Lopez
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D005699:Galactosylceramides / Q000633:toxicity; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D047495:PPAR gamma / Q000819:agonists*; D011247:Pregnancy; D047928:Premature Birth / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D005699:Galactosylceramides; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C493154:alpha-galactosylceramide; D000077154:Rosiglitazone