Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes.

Autor:	Farias-Jofre M; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Division of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile., Romero R; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA. Electronic address: romeror@mail.nih.gov., Galaz J; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Division of Obstetrics and Gynecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile., Xu Y; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA., Miller D; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA., Garcia-Flores V; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA., Arenas-Hernandez M; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA., Winters AD; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MO, USA., Berkowitz BA; Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine; Detroit, MI, USA., Podolsky RH; Division of Biostatistics and Design Methodology, Center for Translational Research, Children's National Hospital, Silver Spring, MD, USA., Shen Y; Department of Radiology, School of Medicine, Wayne State University School of Medicine, Detroit, MI, USA., Kanninen T; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA., Panaitescu B; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA., Glazier CR; UCD School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland., Pique-Regi R; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA., Theis KR; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MO, USA., Gomez-Lopez N; Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, 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 (NICHD/NIH/DHHS), Bethesda, MD, USA; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MO, USA; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: nardhy@wustl.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2023 Dec; Vol. 98, pp. 104865. Date of Electronic Publication: 2023 Nov 07.
DOI:	10.1016/j.ebiom.2023.104865
Abstrakt:	Background: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment. Methods: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping. Findings: IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis. Interpretation: IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes. Funding: NICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023. Published by Elsevier B.V.)
Databáze:	MEDLINE
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