Browsing by Author "Podolsky, Robert H."

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    Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes
    (2023) 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
    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.