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Fetal inflammation is associated with persistent systemic and hippocampal inflammation and dysregulation of hippocampal glutamatergic homeostasis.

ABSTRACT: BACKGROUND:Inflammation is a major cause of preterm birth and often results in a fetal inflammatory response syndrome (FIRS). Preterm infants with FIRS have a higher childhood incidence of neurodevelopmental disability than preterm infants without FIRS. The mechanisms connecting FIRS to neurodevelopmental disability in formerly preterm infants are not fully understood, but the effect on premature gray matter may have an important role. METHODS:Fetal rats were exposed to intra-amniotic (i.a.) LPS 2 days prior to birth to model FIRS. On postnatal day 7, expression of inflammatory mediators was measured in the liver, lung, and brain. Activation of microglia and expression of glutamatergic receptor subunits and transporters were measured in the hippocampus and cortex. RESULTS:LPS caused persistent systemic inflammatory mediators gene expression. In the brain, there was corresponding activation of microglia in the hippocampus and cortex. Expression of inflammatory mediators persisted in the hippocampus, but not the cortex, and was associated with altered glutamatergic receptor subunits and transporters. CONCLUSION:Hippocampal inflammation and dysregulation of glutamate metabolism persisted well into the postnatal period following i.a. LPS. Poor neurodevelopmental outcomes after FIRS in preterm infants may result in part through glutamatergically driven gray matter injury to the neonatal hippocampus.

SUBMITTER: Gisslen T

PROVIDER: S-EPMC6435426 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Fetal inflammation is associated with persistent systemic and hippocampal inflammation and dysregulation of hippocampal glutamatergic homeostasis.

Gisslen Tate T Singh Garima G Georgieff Michael K MK

Pediatric research 20190211 5

<h4>Background</h4>Inflammation is a major cause of preterm birth and often results in a fetal inflammatory response syndrome (FIRS). Preterm infants with FIRS have a higher childhood incidence of neurodevelopmental disability than preterm infants without FIRS. The mechanisms connecting FIRS to neurodevelopmental disability in formerly preterm infants are not fully understood, but the effect on premature gray matter may have an important role.<h4>Methods</h4>Fetal rats were exposed to intra-amni ...[more]

PMID: 30745569

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Project description:BackgroundInjection drug use is a growing major public health concern. Injection drug users (IDUs) have a higher incidence of co-morbidities including HIV, Hepatitis, and other infections. An effective humoral response is critical for optimal homeostasis and protection from infection; however, the impact of injection heroin use on humoral immunity is poorly understood. We hypothesized that IDUs have altered B cell and antibody profiles.Methods and findingsA comprehensive systems biology-based cross-sectional assessment of 130 peripheral blood B cell flow cytometry- and plasma- based features was performed on HIV-/Hepatitis C-, active heroin IDUs who participated in a syringe exchange program (n = 19) and healthy control subjects (n = 19). The IDU group had substantial polydrug use, with 89% reporting cocaine injection within the preceding month. IDUs exhibited a significant, 2-fold increase in total B cells compared to healthy subjects, which was associated with increased activated B cell subsets. Although plasma total IgG titers were similar between groups, IDUs had significantly higher IgG3 and IgG4, suggestive of chronic B cell activation. Total IgM was also increased in IDUs, as well as HIV Envelope-specific IgM, suggestive of increased HIV exposure. IDUs exhibited numerous features suggestive of systemic inflammation, including significantly increased plasma sCD40L, TNF-?, TGF-?, IL-8, and ceramide metabolites. Machine learning multivariate analysis distilled a set of 10 features that classified samples based on group with absolute accuracy.ConclusionsThese results demonstrate broad alterations in the steady-state humoral profile of IDUs that are associated with increased systemic inflammation. Such dysregulation may impact the ability of IDUs to generate optimal responses to vaccination and infection, or lead to increased risk for inflammation-related co-morbidities, and should be considered when developing immune-based interventions for this growing population.

Project description:BackgroundInflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood.MethodsWe evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community.ResultsAcute malaria was marked by elevated levels of proinflammatory and regulatory cytokines and expansion of the inflammatory "intermediate" monocyte subset that returned to levels of healthy asymptomatic children 6 weeks later. Monocytes displayed activated phenotypes during acute malaria, with changes in surface expression of markers important to innate and adaptive immunity. Functionally, acute malaria monocytes and monocytes from asymptomatic infected children had impaired phagocytosis of P. falciparum-infected erythrocytes relative to asymptomatic children with no blood-stage infection. Monocytes from both acute malaria and recovery time points displayed strong and equivalent cytokine responsiveness to innate immune agonists that were independent of infection status. Monocyte transcriptional profiles revealed regulated and balanced proinflammatory and antiinflammatory and altered phagocytosis gene expression patterns distinct from malaria-naive monocytes.ConclusionThese observations provide insights into monocyte functions and the innate immune response during uncomplicated malaria and suggest that asymptomatic parasitemia in children is not clinically benign.FundingSupport for this work was provided by NIH/National Institute of Allergy and Infectious Diseases (R01AI095192-05), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene, and the Rainbow Babies & Children's Foundation.

Dataset Information

Fetal inflammation is associated with persistent systemic and hippocampal inflammation and dysregulation of hippocampal glutamatergic homeostasis.

Publications

Fetal inflammation is associated with persistent systemic and hippocampal inflammation and dysregulation of hippocampal glutamatergic homeostasis.

Similar Datasets

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