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

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

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Article number	104865
Journal	EBioMedicine
Volume	98
DOIs	https://doi.org/10.1016/j.ebiom.2023.104865
State	Published - Dec 2023

Keywords

Alarmin
IL-1α
Microbiome
Pregnancy
Prematurity
Sterile intra-amniotic inflammation

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10.1016/j.ebiom.2023.104865

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Farias-Jofre, M., Romero, R., Galaz, J., Xu, Y., Miller, D., Garcia-Flores, V., Arenas-Hernandez, M., Winters, A. D., Berkowitz, B. A., Podolsky, R. H., Shen, Y., Kanninen, T., Panaitescu, B., Glazier, C. R., Pique-Regi, R., Theis, K. R., & Gomez-Lopez, N. (2023). Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes. EBioMedicine, 98, Article 104865. https://doi.org/10.1016/j.ebiom.2023.104865

@article{44645b59be1a4c0dab5cca919fa1ab69,

title = "Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes",

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",

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

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = dec,

doi = "10.1016/j.ebiom.2023.104865",

language = "English",

volume = "98",

journal = "EBioMedicine",

issn = "2352-3964",

}

Farias-Jofre, M, Romero, R, Galaz, J, Xu, Y, Miller, D, Garcia-Flores, V, Arenas-Hernandez, M, Winters, AD, Berkowitz, BA, Podolsky, RH, Shen, Y, Kanninen, T, Panaitescu, B, Glazier, CR, Pique-Regi, R, Theis, KR & Gomez-Lopez, N 2023, 'Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes', EBioMedicine, vol. 98, 104865. https://doi.org/10.1016/j.ebiom.2023.104865

TY - JOUR

T1 - Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes

AU - Farias-Jofre, Marcelo

AU - Romero, Roberto

AU - Galaz, Jose

AU - Xu, Yi

AU - Miller, Derek

AU - Garcia-Flores, Valeria

AU - Arenas-Hernandez, Marcia

AU - Winters, Andrew D.

AU - Berkowitz, Bruce A.

AU - Podolsky, Robert H.

AU - Shen, Yimin

AU - Kanninen, Tomi

AU - Panaitescu, Bogdan

AU - Glazier, Catherine R.

AU - Pique-Regi, Roger

AU - Theis, Kevin R.

AU - Gomez-Lopez, Nardhy

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Alarmin

KW - IL-1α

KW - Microbiome

KW - Pregnancy

KW - Prematurity

KW - Sterile intra-amniotic inflammation

UR - http://www.scopus.com/inward/record.url?scp=85175795216&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2023.104865

DO - 10.1016/j.ebiom.2023.104865

M3 - Article

C2 - 37944273

AN - SCOPUS:85175795216

SN - 2352-3964

VL - 98

JO - EBioMedicine

JF - EBioMedicine

M1 - 104865

ER -

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

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Keywords

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