Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes
link https://doi.org/10.1016/j.ebiom.2023.104865account_box Farias-Jofre, Marceloaccount_box Romero, Robertoaccount_box Galaz, Joseaccount_box Xu, Yiaccount_box Miller, Derekaccount_box Garcia-Flores, Valeriaaccount_box Arenas-Hernandez, Marciaaccount_box Winters, Andrew D.account_box Berkowitz, Bruce A.account_box Podolsky, Robert H.account_box Shen, Yiminaccount_box Kanninen, Tomiaccount_box Panaitescu, Bogdanaccount_box Glazier, Catherine R.account_box Pique-Regi, Rogeraccount_box Theis, Kevin R.account_box Gomez-Lopez, Nardhy
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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-1 alpha in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1 alpha. 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-1 alpha. Intra-amniotic injection of IL-1 alpha 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-1 alpha exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1 alpha-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.
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| Autor | Farias-Jofre, Marcelo Romero, Roberto Galaz, Jose Xu, Yi Miller, Derek Garcia-Flores, Valeria Arenas-Hernandez, Marcia Winters, Andrew D. Berkowitz, Bruce A. Podolsky, Robert H. Shen, Yimin Kanninen, Tomi Panaitescu, Bogdan Glazier, Catherine R. Pique-Regi, Roger Theis, Kevin R. Gomez-Lopez, Nardhy |
| Título | Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes |
| Revista | Ebiomedicine |
| ISSN | 2352-3964 |
| Volumen | 98 |
| Fecha de publicación | 2023 |
| Resumen | 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-1 alpha in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1 alpha. 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-1 alpha. Intra-amniotic injection of IL-1 alpha 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-1 alpha exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1 alpha-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. |
| Derechos | acceso restringido |
| DOI | 10.1016/j.ebiom.2023.104865 |
| Enlace | |
| Id de publicación en WoS | WOS:001110459700001 |
| Palabra clave | Alarmin IL-1 alpha Microbiome Pregnancy Prematurity Sterile intra-amniotic inflammation |
| Tema ODS | 03 Good Health and Well-being 05 Gender Equality |
| Tema ODS español | 03 Salud y bienestar 05 Igualdad de género |
| Tipo de documento | artículo |