The fetal response to maternal inflammation is dependent upon maternal IL-6 in a murine model

Bermick, Jennifer; Watson, Sarah N.; Lueschow, Shiloh R.; McElroy, Steven J.

doi:10.1016/j.cyto.2023.156210

Cited by 8 publications

(7 citation statements)

References 52 publications

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“…There is no consensus on the role of inflammatory markers in the identification of chorioamnionitis in women because of the low sensitivity and specificity of laboratory indicators of maternal blood when applied alone in previous studies [ 10 , 12 , 13 , 27 ]. Higher levels of cytokines in maternal serum indicate that the maternal compartment is the primary inflammatory source [ 28 ], and maternally derived inflammatory factors may directly induce fetal injury [ 29 ]. The inflammatory markers explored in this study were designed precisely to capitalize on differences in levels of inflammatory factors to identify the occurrence of acute HCA in febrile women receiving epidural analgesia.…”

Section: Discussionmentioning

confidence: 99%

Laboratory markers to identify acute histological chorioamnionitis in febrile parturients undergoing epidural analgesia: a retrospective study

Xu,

Fan,

Zhang

et al. 2023

BMC Pregnancy Childbirth

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Background This study aimed to investigate the effect of the pathological staging of acute histological chorioamnionitis (HCA) on laboratory indicators and to conduct further studies to reassess the threshold values used by clinicians to identify acute HCA in febrile parturients undergoing epidural analgesia. Methods A retrospective study of febrile mothers receiving epidural analgesia at Nanjing Maternal and Child Health Care Hospital from January 1, 2018 to December 31, 2018. The participants were grouped by the progression of acute HCA, and the laboratory parameters were compared between groups. The ability of C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and monocyte-leukocyte ratio (M%), alone or in combination, to identify acute HCA in febrile parturients undergoing epidural analgesia was assessed using logistic regression and ROC curves. Results The area under the curve (AUC) of the best logistic regression model predicting HCA climbed to 0.706 (CRP + MLR). Maternal CRP, NLR, and MLR significantly and progressively increased with the progression of acute HCA (p < 0.0001). Based on the ROC curves, the following thresholds were selected to define increased laboratory indicators for identifying acute HCA: CRP ≥ 6.90 mg/L, NLR ≥ 11.93, and MLR ≥ 0.57. In addition, the AUC of the best logistic regression model predicting HCA ≥ stage 2 was 0.710, so these inflammatory markers were more precise in predicting HCA ≥ stage 2. Conclusion Increased CRP (≥ 6.90 mg/L), NLR (≥ 11.93), and MLR (≥ 0.57) may help clinicians to identify early potential acute HCA in febrile parturients receiving epidural analgesia and to monitor progression to optimize clinical treatment options. Trial registration The study was registered in the Chinese Clinical Trial Registry on November 24, 2021 (http://www.chictr.org.cn, ChiCTR2100053554).

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Section: Discussionmentioning

confidence: 99%

Laboratory markers to identify acute histological chorioamnionitis in febrile parturients undergoing epidural analgesia: a retrospective study

Xu,

Fan,

Zhang

et al. 2023

BMC Pregnancy Childbirth

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“…Differences in plasma IL-6 levels could be due to variation in the timing of sample collection ( Cui et al, 2011 ) or LPS serotype or dose ( Alexander & Fewell, 2011 ). While Hsiao and Patterson (2011 ) showed that offspring exposed to gestational IL-6 alone developed schizophrenia- and autism-like behavioral changes consistent with those present in offspring exposed to MIA via the viral mimic poly(I:C), Bermick and colleagues (2023) showed that maternal IL-6 does not directly cross into fetal circulation but stimulates an independent fetal IL-6 response. Among offspring in our study, IL-6R expression was greater in MIA-exposed male fetal brains.…”

Section: Discussionmentioning

confidence: 79%

Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Martz,

Shelton,

Geist

et al. 2023

Preprint

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Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11β-hydroxylase inhibitor used to treat hypercortisolism in pregnant and neonatal populations. Maternal, placental, and fetal CNS levels of corticosterone and placental 11βHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11βHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in the ventral hippocampus of adult males, but not females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

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“…Combining these rodent findings with our human-centric data implies that IL-6 trans-signalling to neural progenitor cells and neurons may not be the direct, central pathogenic mechanism in the CNS of both species and makes the case for the use of a more complex 3D model that contains additional relevant cell types when studying the effects of IL-6 on developing neurons. Moreover, while hiPSCs provide a valuable model for studying human neurodevelopment within a human-relevant context at a molecular scale, they do not fully capture the complex interactions between additional higher-level systems seen in vivo, such as the peripheral immune system, placenta and blood brain barrier, which would be relevant in the context of this study (Zaretsky et al ., 2004; Campbell et al ., 2014; Crockett et al ., 2021; Li et al ., 2021, 2023; Bermick et al ., 2023). This is especially apparent since a recent MIA rodent model demonstrated IL-6 is not expected to pass through the placenta from the mother (Bermick et al ., 2023), even the IL-6 molecule can pass through human placental tissue (Zaretsky et al ., 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, while hiPSCs provide a valuable model for studying human neurodevelopment within a human-relevant context at a molecular scale, they do not fully capture the complex interactions between additional higher-level systems seen in vivo, such as the peripheral immune system, placenta and blood brain barrier, which would be relevant in the context of this study (Zaretsky et al ., 2004; Campbell et al ., 2014; Crockett et al ., 2021; Li et al ., 2021, 2023; Bermick et al ., 2023). This is especially apparent since a recent MIA rodent model demonstrated IL-6 is not expected to pass through the placenta from the mother (Bermick et al ., 2023), even the IL-6 molecule can pass through human placental tissue (Zaretsky et al ., 2004). It is more likely that increased maternal prenatal IL-6 sets off a larger, pro-inflammatory chain reaction involving multiple cytokines, cell-types and tissues that subsequently in-directly increases IL-6 in the foetal brain.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and Cellular Response of hiPSC-derived Microglia-Neural Progenitor Co-Cultures Exposed to IL-6

Couch,

Brown,

Raimundo

et al. 2023

Preprint

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Elevated interleukin (IL-)6 levels during prenatal development have been linked to increased risk for neurodevelopmental disorders (NDD) in the offspring, but the mechanism remains unclear. Human-induced pluripotent stem cell (hiPSC) models offer a valuable tool to study the effects of IL-6 on features relevant for human neurodevelopmentin vitro. We previously reported that hiPSC-derived microglia-like cells (MGLs) respond to IL-6, but neural progenitor cells (NPCs) in monoculture do not. We therefore investigated whether co-culturing hiPSC-derived MGLs with NPCs would trigger a cellular response to IL-6 stimulation via secreted factors from the MGLs. Using N=4 donor lines without psychiatric diagnosis, we first confirmed that NPCs can respond to IL-6 through trans-signalling when recombinant IL-6Ra is present, and that this response is dose-dependent. In response to IL-6, MGLs secreted soluble IL-6R, but at lower levels than found in vivo and below that needed to activate trans-signalling in NPCs. Among other cytokines, MGLs also increased Tumour necrosis factor (TNF)α secretion into the co-culture environment. Despite this, whilst transcriptomic analysis confirmed that MGLs undergo substantial transcriptomic changes after IL-6 exposure, NPCs in co-culture with MGLs exhibited a minimal transcriptional response. Furthermore, there were no significant cell fate-acquisition changes when differentiated into post-mitotic cultures, nor alterations in synaptic densities in mature neurons. These findings highlight the need to investigate if trans-IL-6 signalling to NPCs is a relevant disease mechanism linking prenatal IL-6 exposure to increased risk for psychiatric disorders. Moreover, our findings underscore the importance of establishing more complexin vitrohuman models with diverse cell types, which may show cell-specific responses to microglia-released cytokines to fully understand how IL-6 exposure may influence human neurodevelopment.

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The fetal response to maternal inflammation is dependent upon maternal IL-6 in a murine model

Cited by 8 publications

References 52 publications

Laboratory markers to identify acute histological chorioamnionitis in febrile parturients undergoing epidural analgesia: a retrospective study

Laboratory markers to identify acute histological chorioamnionitis in febrile parturients undergoing epidural analgesia: a retrospective study

Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Transcriptional and Cellular Response of hiPSC-derived Microglia-Neural Progenitor Co-Cultures Exposed to IL-6

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