Associations between maternal cytokine levels during gestation and measures of child cognitive abilities and executive functioning

Dozmorov, Mikhail G.; Bilbo, Staci D.; Kollins, Scott H.; Zucker, Nancy; Elizabeth, K.; Schechter, Julia C.; Zhang, Junfeng Jim; Murphy, Susan K.; Hoyo, Cathrine; Fuemmeler, Bernard F.

doi:10.1016/j.bbi.2018.03.029

Cited by 35 publications

(30 citation statements)

References 46 publications

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“…The perinatal period is critical for brain development. Dysregulation of maternal cytokine levels during gestation has been associated with disturbances of motor and cognitive development, leading, for instance, to cerebral palsy, learning impairments, or autism spectrum disorders 48,49 . We previously showed using the same model that in-utero GBS-exposed rats presented sexually dichotomous impairments characterised by early autistic-like traits in males – but not in females – associated with forebrain white matter tract alterations 32 .…”

Section: Discussionmentioning

confidence: 99%

Sex-specific maternofetal innate immune responses triggered by group B Streptococci

Allard

Giraud

Segura

et al. 2019

Sci Rep

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Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis, which is a major risk factor for premature birth and brain injuries. Males are at greater risk than females for developing lifelong neurobehavioural disorders, although the origins of this sex bias remain poorly understood. We previously showed that end-gestational inflammation triggered by GBS led to early neurodevelopmental impairments mainly in the male rat progeny. Identifying key inflammatory players involved in maternofetal immune activation by specific pathogens is critical to develop appropriate novel therapeutic interventions. We aimed to map out the GBS-induced profile of innate immune biomarkers in the maternal-placental-fetal axis, and to compare this immune profile between male and female tissues. We describe here that the GBS-induced immune signalling involved significantly higher levels of interleukin (IL)-1β, cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1) and polymorphonuclear cells (PMNs) infiltration in male compared to female maternofetal tissues. Although male – but not female – fetuses presented increased levels of IL-1β, fetuses from both sexes in-utero exposed to GBS had increased levels of TNF-α in their circulation. Levels of IL-1β detected in fetal sera correlated positively with the levels found in maternal circulation. Here, we report for the first time that the maternofetal innate immune signalling induced by GBS presents a sexually dichotomous profile, with more prominent inflammation in males than females. These sex-specific placental and fetal pro-inflammatory responses are in keeping with the higher susceptibility of the male population for preterm birth, brain injuries and neurodevelopmental disorders such as cerebral palsy and autism spectrum disorders.

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Section: Discussionmentioning

confidence: 99%

Sex-specific maternofetal innate immune responses triggered by group B Streptococci

Allard

Giraud

Segura

et al. 2019

Sci Rep

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“…A more recent series of studies using this model pinpoints the role of maternal Th17 cell-derived IL-17a as critical in producing a striking cortical patching phenotype in offspring, alongside autism-like behavioral abnormalities [34–36]. In contrast to these pre-clinical data, a recent study in humans links high levels of maternal IL-17a during the first trimester to better cognitive outcomes in children by 4 years of age, rather than the opposite [37]. Nonetheless, this is a promising avenue of research, as IL-17a could be an important therapeutic target to pursue.…”

Section: Environmental Factors Affecting Microglial Developmentmentioning

confidence: 99%

Environment matters: microglia function and dysfunction in a changing world

Hanamsagar

Bilbo

2017

Current Opinion in Neurobiology

107

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The immune system is our interface with the environment, and immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy or the early postnatal period, e.g. in response to infection, may disrupt the normal developmental trajectory of microglia and consequently their interactions with neurons, thereby contributing to the risk for neurological disorders. The current article outlines recent findings on the impact of diverse, pervasive environmental challenges, beyond infection, including air pollution and maternal stress; and their impact on microglial development and its broad implications for neural pathologies.

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“…Common to these conditions are increased levels of maternal cytokines. Studies of multiple independent cohorts have identified an association between altered maternal gestational serum cytokines and adverse neurodevelopmental outcomes in the child [ 10 , 11 ]. In experimental models, MIA increases levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, IL-17A, and interferon-gamma (IFN-γ) in maternal serum, the placenta, amniotic fluid, and fetal brain after immune insult [ 8 , 12 – 15 ], and specific cytokines, for example IL-1 [ 16 ], IL-6 [ 17 ], and IL-17A [ 13 ], have been identified as essential in mediating the effects of MIA on offspring behavior.…”

Section: Introductionmentioning

confidence: 99%

Effects of cytokines on nuclear factor-kappa B, cell viability, and synaptic connectivity in a human neuronal cell line

et al. 2020

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Maternal infection during pregnancy is associated with increased risk of psychiatric and neurodevelopmental disorders (NDDs). Experimental animal models demonstrate that maternal immune activation (MIA) elevates inflammatory cytokine levels in the maternal and fetal compartments and causes behavioral changes in offspring. Individual cytokines have been shown to modulate neurite outgrowth and synaptic connectivity in cultured rodent neurons, but whether clinically relevant cytokine mixtures similarly modulate neurodevelopment in human neurons is not known. To address this, we quantified apoptosis, neurite outgrowth, and synapse number in the LUHMES human neuronal cell line exposed to varying concentrations of: (1) a mixture of 12 cytokines and chemokines (EMA) elevated in mid-gestational serum samples from mothers of children with autism and intellectual disability; (2) an inflammatory cytokine mixture (ICM) comprised of 5 cytokines elevated in experimental MIA models; or (3) individual cytokines in ICM. At concentrations that activated nuclear factor-kappa B (NF-κB) in LUHMES cells, EMA and ICM induced caspase-3/7 activity. ICM altered neurite outgrowth, but only at concentrations that also reduced cell viability, whereas ICM reduced synapse number independent of changes in cell viability. Individual cytokines in ICM phenocopied the effects of ICM on NF-κB activation and synaptic connectivity, but did not completely mimic the effects of ICM on apoptosis. These results demonstrate that clinically relevant cytokine mixtures modulate apoptosis and synaptic density in developing human neurons. Given the relevance of these neurodevelopmental processes in NDDs, our findings support the hypothesis that cytokines contribute to the adverse effects of MIA on children.

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Associations between maternal cytokine levels during gestation and measures of child cognitive abilities and executive functioning

Cited by 35 publications

References 46 publications

Sex-specific maternofetal innate immune responses triggered by group B Streptococci

Sex-specific maternofetal innate immune responses triggered by group B Streptococci

Environment matters: microglia function and dysfunction in a changing world

Effects of cytokines on nuclear factor-kappa B, cell viability, and synaptic connectivity in a human neuronal cell line

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