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

Marcelo Farias-Jofre; Roberto Romero; Jose Galaz; Yi Xu; Derek Miller; Valeria Garcia-Flores; Marcia Arenas-Hernandez; Andrew D Winters; Bruce A Berkowitz; Robert H Podolsky; Yimin Shen; Tomi Kanninen; Bogdan Panaitescu; Catherine R Glazier; Roger Pique-Regi; Kevin R Theis; Nardhy Gomez-Lopez

doi:10.1016/j.ebiom.2023.104865

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

EBioMedicine. 2023 Dec:98:104865. doi: 10.1016/j.ebiom.2023.104865. Epub 2023 Nov 7.

Authors

Marcelo Farias-Jofre¹, Roberto Romero², Jose Galaz¹, Yi Xu³, Derek Miller⁴, Valeria Garcia-Flores⁴, Marcia Arenas-Hernandez³, Andrew D Winters⁵, Bruce A Berkowitz⁶, Robert H Podolsky⁷, Yimin Shen⁸, Tomi Kanninen³, Bogdan Panaitescu³, Catherine R Glazier⁹, Roger Pique-Regi¹⁰, Kevin R Theis¹¹, Nardhy Gomez-Lopez¹²

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine; Detroit, MI, USA.
⁷ Division of Biostatistics and Design Methodology, Center for Translational Research, Children's National Hospital, Silver Spring, MD, USA.
⁸ Department of Radiology, School of Medicine, Wayne State University School of Medicine, Detroit, MI, USA.
⁹ UCD School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
¹⁰ 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.
¹¹ 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.
¹² 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.

Abstract

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.

Keywords: Alarmin; IL-1α; Microbiome; Pregnancy; Prematurity; Sterile intra-amniotic inflammation.

MeSH terms

Amniotic Fluid
Animals
Antibodies, Monoclonal / therapeutic use
Child
Female
Humans
Infant, Newborn
Inflammation / metabolism
Interleukin-6 / metabolism
Mice
Pregnancy
Premature Birth* / prevention & control
Proteomics
Receptors, Interleukin-6* / antagonists & inhibitors

Substances

Interleukin-6
Receptors, Interleukin-6
Antibodies, Monoclonal

Grants and funding

HHSN275201300006C/HD/NICHD NIH HHS/United States