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

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dc.contributor.authorFarias-Jofre, Marcelo
dc.contributor.authorRomero, Roberto
dc.contributor.authorGalaz, Jose
dc.contributor.authorXu, Yi
dc.contributor.authorMiller, Derek
dc.contributor.authorGarcia-Flores, Valeria
dc.contributor.authorArenas-Hernandez, Marcia
dc.contributor.authorWinters, Andrew D.
dc.contributor.authorBerkowitz, Bruce A.
dc.contributor.authorPodolsky, Robert H.
dc.contributor.authorShen, Yimin
dc.contributor.authorKanninen, Tomi
dc.contributor.authorPanaitescu, Bogdan
dc.contributor.authorGlazier, Catherine R.
dc.contributor.authorPique-Regi, Roger
dc.contributor.authorTheis, Kevin R.
dc.contributor.authorGomez-Lopez, Nardhy
dc.date.accessioned2025-01-20T17:23:03Z
dc.date.available2025-01-20T17:23:03Z
dc.date.issued2023
dc.description.abstractBackground 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.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.ebiom.2023.104865
dc.identifier.issn2352-3964
dc.identifier.urihttps://doi.org/10.1016/j.ebiom.2023.104865
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/91496
dc.identifier.wosidWOS:001110459700001
dc.language.isoen
dc.revistaEbiomedicine
dc.rightsacceso restringido
dc.subjectAlarmin
dc.subjectIL-1 alpha
dc.subjectMicrobiome
dc.subjectPregnancy
dc.subjectPrematurity
dc.subjectSterile intra-amniotic inflammation
dc.subject.ods03 Good Health and Well-being
dc.subject.ods05 Gender Equality
dc.subject.odspa03 Salud y bienestar
dc.subject.odspa05 Igualdad de género
dc.titleBlockade of IL-6R prevents preterm birth and adverse neonatal outcomes
dc.typeartículo
dc.volumen98
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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