In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes

Matta, Poojitha; Sherrod, Stacy D.; Marasco, Christina C.; Moore, Daniel J.; McLean, John A.; Weitkamp, Jörn-Hendrik

doi:10.4049/jimmunol.1601880

Cited by 12 publications

(9 citation statements)

References 77 publications

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“…It is true that chorioamnionitis is more prevalent in preterm births, but it still complicates up to 4% of term deliveries . Studies focusing on neonatal adaptive immunity have shown that chorioamnionitis exposure amplifies Th17‐ and Th1‐type responses in preterm infants . A study focusing on both innate and adaptive immunity employed a broad transcriptomic approach, using a microarray to evaluate mRNA expression in whole blood of preterm neonates with and without chorioamnionitis exposure .…”

Section: Discussionmentioning

confidence: 99%

Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes

et al. 2018

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Chorioamnionitis is an intrauterine infection involving inflammation of the chorion, amnion and placenta. It leads to a fetal systemic inflammatory response that can alter the transcription of neonatal immune genes. We have previously shown that neonatal monocytes gain the activating histone tail modification H3K4me3 at promoters of immunologically important genes as development progresses from preterm neonate to adult. In this study, we applied ChIP-seq and RNA-seq to evaluate the impact of chorioamnionitis on the neonatal monocyte H3K4me3 histone modification landscape over the course of fetal and neonatal immune system development. Chorioamnionitis exposure in neonatal monocytes resulted in a net increase in total monocyte H3K4me3, primarily in introns and intergenic regions. Immune gene expression was decreased in chorioamnionitis-exposed monocytes, with the majority of enriched transcripts falling into pathways that are not linked to the immune system. Over half of all neonatal monocyte H3K4me3 peaks, independent of their location, were associated with active gene transcription. Overall, chorioamnionitis exposure resulted in global remodeling of the neonatal monocyte H3K4me3 landscape and changes in the expression of known immune genes. These changes resulted in a less robust inflammatory response upon exposure to a secondary challenge, which may explain why chorioamnionitis-exposed neonates have an increased risk of sepsis.

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Section: Discussionmentioning

confidence: 99%

Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes

et al. 2018

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“…Increased concentrations of amniotic fluid cytokines and chemokines are associated with fetal damage (146)(147)(148)(149), indicating that inflammation can negatively impact the offspring (150,151), namely fetal growth restriction (152). Thus, we followed up our amniotic fluid cytokine determinations with the evaluation of fetal growth parameters.…”

Section: In Vivo T Cell Activation Induces Intra-amniotic Inflammatiomentioning

confidence: 99%

Effector and Activated T Cells Induce Preterm Labor and Birth That Is Prevented by Treatment with Progesterone

Arenas‐Hernandez

Romero

et al. 2019

The Journal of Immunology

114

109

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Preterm labor commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. Most research has focused on establishing a causal link between innate immune activation and pathological inflammation leading to preterm labor and birth. However, the role of maternal effector/activated T cells in the pathogenesis of preterm labor/birth is poorly understood. In this study, we first demonstrated that effector memory and activated maternal T cells expressing granzyme B and perforin are enriched at the maternal-fetal interface (decidua) of women with spontaneous preterm labor. Next, using a murine model, we reported that prior to inducing preterm birth, in vivo T cell activation caused maternal hypothermia, bradycardia, systemic inflammation, cervical dilation, intra-amniotic inflammation, and fetal growth restriction, all of which are clinical signs associated with preterm labor. In vivo T cell activation also induced B cell cytokine responses, a proinflammatory macrophage polarization, and other inflammatory responses at the maternal-fetal interface and myometrium in the absence of an increased influx of neutrophils. Finally, we showed that treatment with progesterone can serve as a strategy to prevent preterm labor/birth and adverse neonatal outcomes by attenuating the proinflammatory responses at the maternal-fetal interface and cervix induced by T cell activation. Collectively, these findings provide mechanistic evidence showing that effector and activated T cells cause pathological inflammation at the maternal-fetal interface, in the mother, and in the fetus, inducing preterm labor and birth and adverse neonatal outcomes. Such adverse effects can be prevented by treatment with progesterone, a clinically approved strategy.

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“…Chorioamnionitis exposure has been reported by several groups to drive the emergence of circulating T-effector memory cells (CD4 + CD25 lo CD127 hi ), with a Th1/Th17-like phenotype (126,(137)(138)(139), although one study did not find such a difference (66). Chorioamnionitis also changed the metabolic profile of CD4 + T cells, altering metabolites that are part of the tryptophan catabolism and glutathione detoxification pathway, which could be linked to the enhanced development of a Th1 response (137). Enhanced CD4 production of IL-6 has also been reported (137,140).…”

Section: Fetal Systemic Immune Consequences Of Chorioamnionitismentioning

confidence: 99%

“…Chorioamnionitis also changed the metabolic profile of CD4 + T cells, altering metabolites that are part of the tryptophan catabolism and glutathione detoxification pathway, which could be linked to the enhanced development of a Th1 response (137). Enhanced CD4 production of IL-6 has also been reported (137,140). The mechanisms driving the presence of activated T cells in the context of chorioamnionitis remain unclear, though a recent report showed increased number of activated maternal alloantigen-responsive T cells in preterm infants (141).…”

Section: Fetal Systemic Immune Consequences Of Chorioamnionitismentioning

confidence: 99%

Pulmonary Consequences of Prenatal Inflammatory Exposures: Clinical Perspective and Review of Basic Immunological Mechanisms

et al. 2020

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Chorioamnionitis, a potentially serious inflammatory complication of pregnancy, is associated with the development of an inflammatory milieu within the amniotic fluid surrounding the developing fetus. When chorioamnionitis occurs, the fetal lung finds itself in the unique position of being constantly exposed to the consequent inflammatory meditators and/or microbial products found in the amniotic fluid. This exposure results in significant changes to the fetal lung, such as increased leukocyte infiltration, altered cytokine, and surfactant production, and diminished alveolarization. These alterations can have potentially lasting impacts on lung development and function. However, studies to date have only begun to elucidate the association between such inflammatory exposures and lifelong consequences such as lung dysfunction. In this review, we discuss the pathogenesis of and fetal immune response to chorioamnionitis, detail the consequences of chorioamnionitis exposure on the developing fetal lung, highlighting the various animal models that have contributed to our current understanding and discuss the importance of fetal exposures in regard to the development of chronic respiratory disease. Finally, we focus on the clinical, basic, and therapeutic challenges in fetal inflammatory injury to the lung, and propose next steps and future directions to improve our therapeutic understanding of this important perinatal stress.

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In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes

Cited by 12 publications

References 77 publications

Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes

Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes

Effector and Activated T Cells Induce Preterm Labor and Birth That Is Prevented by Treatment with Progesterone

Pulmonary Consequences of Prenatal Inflammatory Exposures: Clinical Perspective and Review of Basic Immunological Mechanisms

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