title: An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment.
abstract: Decidual macrophages are implicated in the local inflammatory response that accompanies spontaneous preterm labor/birth; however, their role is poorly understood. We hypothesized that decidual macrophages undergo a proinflammatory (M1) polarization during spontaneous preterm labor and that PPARγ activation via rosiglitazone (RSG) would attenuate the macrophage-mediated inflammatory response, preventing preterm birth. In this study, we show that: 1) decidual macrophages undergo an M1-like polarization during spontaneous term and preterm labor; 2) anti-inflammatory (M2)-like macrophages are more abundant than M1-like macrophages in decidual tissue; 3) decidual M2-like macrophages are reduced in preterm pregnancies compared with term pregnancies, regardless of the presence of labor; 4) decidual macrophages express high levels of TNF and IL-12 but low levels of peroxisome proliferator-activated receptor γ (PPARγ) during spontaneous preterm labor; 5) decidual macrophages from women who underwent spontaneous preterm labor display plasticity by M1↔M2 polarization in vitro; 6) incubation with RSG reduces the expression of TNF and IL-12 in decidual macrophages from women who underwent spontaneous preterm labor; and 7) treatment with RSG reduces the rate of LPS-induced preterm birth and improves neonatal outcomes by reducing the systemic proinflammatory response and downregulating mRNA and protein expression of NF-κB, TNF, and IL-10 in decidual and myometrial macrophages in C57BL/6J mice. In summary, we demonstrated that decidual M1-like macrophages are associated with spontaneous preterm labor and that PPARγ activation via RSG can attenuate the macrophage-mediated proinflammatory response, preventing preterm birth and improving neonatal outcomes. These findings suggest that the PPARγ pathway is a new molecular target for future preventative strategies for spontaneous preterm labor/birth.
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA.|Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Kadam
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Tara N
authors.initials: TN
authors.lastname: Mial
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.
authors.forename: Olesya
authors.initials: O
authors.lastname: Plazyo
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Garcia-Flores
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Xu
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Adi L
authors.initials: AL
authors.lastname: Tarca
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Sascha
authors.initials: S
authors.lastname: Drewlo
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, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA.|Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.|Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Nardhy
authors.initials: N
authors.lastname: Gomez-Lopez
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002469:Cell Separation; D003656:Decidua / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016130:Immunophenotyping; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D007752:Obstetric Labor, Premature / Q000276:immunology*; D047495:PPAR gamma / Q000819:agonists; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone