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

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

doi:10.1016/j.ebiom.2023.104865

Cited by 8 publications

(8 citation statements)

References 139 publications

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“…Therefore, we next explored inflammatory gene expression in the fetal intestine following an intra-amniotic injection of HMGB1. This revealed alterations in inflammatory gene expression (Supplementary Figure 8), consistent with our previous reports on in utero inflammation 55,56 . Unlike in the fetal lung, the inflammatory milieu in the fetal intestine was downregulated, suggesting that in utero sterile inflammation exerts different effects across fetal organs.…”

Section: Resultssupporting

confidence: 91%

“…Thus, even a relatively brief exposure to in utero sterile inflammation imprints fetal tissue alterations that can be carried over to neonatal life, independently of gestational age at delivery. This concept is supported by previous research demonstrating that prenatal treatments or exposures during gestation can induce permanent changes in neonatal life 75,88–90 . Of interest, recent research employing a transient gestational infection model revealed the role of the IL-6/Th17 axis in augmenting offspring gut immunity, indicating that prenatal immunological events can induce long-lasting effects 89 .…”

Section: Discussionsupporting

confidence: 61%

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Homeostatic macrophages prevent preterm birth and improve neonatal outcomes by mitigatingin uterosterile inflammation

Garcia‐Flores

Liu

Romero

et al. 2023

Preprint

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Preterm birth (PTB), commonly preceded by preterm labor, is the leading cause of neonatal morbidity and mortality worldwide. Recent advances in next-generation sequencing have revealed that most cases of preterm labor are associated with sterile intra-amniotic inflammation (SIAI), an inflammatory condition without detectable microorganisms. To date, no successful strategies to treat SIAI have been developed. Herein, we present mechanistic proof that treatment with M2-polarized macrophages (M2 Mϕ) can effectively prevent SIAI-induced PTB and neonatal mortality. M2 Mϕ halt the premature pathway of labor by infiltrating maternal and fetal compartments, where they inhibit NLRP3 inflammasome activation triggered by HMGB1. Furthermore, M2 Mϕ dampen the HMGB1-induced inflammatory response in the amniotic cavity and fetal lung. Notably, neonates exposed to HMGB1in uterodisplay a reduced capacity to clear bacterial infection and gut microbiome dysbiosis, which are restored by M2 Mϕ treatment. Our findings provide cogent evidence that M2 Mϕ can serve as a cellular strategy to mitigate PTB and decrease neonatal mortality.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 61%

Homeostatic macrophages prevent preterm birth and improve neonatal outcomes by mitigatingin uterosterile inflammation

Garcia‐Flores

Liu

Romero

et al. 2023

Preprint

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“…We previously reported that LPS-induced IUI does not cause preterm birth in Rhesus macaque ( 14 ). There is strong evidence in mice that both normal parturition (inflammation is involved in normal parturition) and inflammation-mediated preterm birth is decreased in the absence of IL6 signaling ( 11 – 13 , 52 ). These studies used transgenic (IL6 knock out) or IL6R inhibitors to eliminate/knock down IL6 signaling.…”

Section: Discussionmentioning

confidence: 99%

IL-1 and TNF mediates IL-6 signaling at the maternal-fetal interface during intrauterine inflammation

Presicce,

Roland,

Senthamaraikannan

et al. 2024

Front. Immunol.

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IntroductionIL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP).MethodsPregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation.ResultsIUI induced a robust expression of IL6 mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of IL6 mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, ADAM17 (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and IL6R mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced IL6 mRNAs in the AMC and variably decreased elements of IL6 trans-signaling.DiscussionThese data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.

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“…Naïve T cells can also acquire memory T-cell markers and functional properties during cytokine-driven proliferation independent of antigen encounter 81 . Previous studies report that asymptomatic maternal SARS-CoV-2 infection resulted in dampened TH1 and TH17 responses and reduced T cell repertoire diversity that does not extend to neonatal circulation 14 . Here, stimulation of neonatal T cells from the maternal SARS+ group resulted in a dampened response to anti-CD3/CD28 stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…While some studies have described the presence of SARS-CoV-2 RNA in placental villi, including maternal macrophages and Hofbauer cells (HBC) [5][6][7] , vertical transmission is extremely rare [8][9][10][11] . Nevertheless, SARS-CoV-2 infection during pregnancy has been shown to alter frequencies of macrophage and effector T-cell subsets and induce a pro-inflammatory environment at the maternal-fetal interface (MFI), specifically within the maternal decidua [12][13][14] . Moreover, pregnant women with severe COVID-19 are more likely to give birth to newborns with morbidities including respiratory distress syndrome 15,16 , hyperbilirubinemia [16][17][18] , sepsis 16,[19][20][21] , infections requiring antibiotic treatments 22 , and admission to the neonatal intensive care unit (NICU) 16,20,23 .…”

Section: Introductionmentioning

confidence: 99%

Mild/Asymptomatic Maternal SARS-CoV-2 Infection Leads to Immune Paralysis in Fetal Circulation and Immune Dysregulation in Fetal-Placental Tissues

Doratt

Sureshchandra

True

et al. 2023

Preprint

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Few studies have addressed the impact of maternal mild/asymptomatic SARS-CoV-2 infection on the developing neonatal immune system. In this study, we analyzed umbilical cord blood and placental chorionic villi from newborns of unvaccinated mothers with mild/asymptomatic SARS-CoV-2 infection during pregnancy using flow cytometry, single-cell transcriptomics, and functional assays. Despite the lack of vertical transmission, levels of inflammatory mediators were altered in cord blood. Maternal infection was also associated with increased memory T, B cells, and non-classical monocytes as well as increased activation. However, ex vivo responses to stimulation were attenuated. Finally, within the placental villi, we report an expansion of fetal Hofbauer cells and infiltrating maternal macrophages and rewiring towards a heightened inflammatory state. In contrast to cord blood monocytes, placental myeloid cells were primed for heightened antiviral responses. Taken together, this study highlights dysregulated fetal immune cell responses in response to mild maternal SARS-CoV-2 infection during pregnancy.

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

Cited by 8 publications

References 139 publications

Homeostatic macrophages prevent preterm birth and improve neonatal outcomes by mitigatingin uterosterile inflammation

Homeostatic macrophages prevent preterm birth and improve neonatal outcomes by mitigatingin uterosterile inflammation

IL-1 and TNF mediates IL-6 signaling at the maternal-fetal interface during intrauterine inflammation

Mild/Asymptomatic Maternal SARS-CoV-2 Infection Leads to Immune Paralysis in Fetal Circulation and Immune Dysregulation in Fetal-Placental Tissues

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