Pre-eclampsia and neuronal development: the potential pathogenic role of inflammation

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dc.check.date2029-12-31
dc.contributor.advisorO'Keeffe, Gerard W.
dc.contributor.advisorMcCarthy, Cathal
dc.contributor.advisorexternalTuulari, Jetro
dc.contributor.advisorexternalKarlsson, Linnea
dc.contributor.advisorexternalKarlsson, Hasse
dc.contributor.authorBarron, Aaronen
dc.contributor.funderIrish Research Council for Science, Engineering and Technology
dc.date.accessioned2024-09-25T09:33:41Z
dc.date.available2024-09-25T09:33:41Z
dc.date.issued2024
dc.date.submitted2024
dc.description.abstractBackground: Pre-eclampsia (PE) is a common and serious hypertensive disorder of pregnancy that occurs in approximately 3-5% of first-time pregnancies. There is increasing evidence that in utero exposure to PE increases the risk for various neurodevelopmental disorders, particularly autism spectrum disorder and attention-deficit/hyperactivity disorder ADHD, although the mechanism(s) mediating this relationship are yet to be elucidated. Chapter 1 of this thesis describes the evidence implicating a causal role for PE exposure in the aetiology of various neurodevelopmental disorders and neuroanatomical alterations in the small number of imaging studies that have been undertaken in this context. It then postulates that inflammation, a prominent pathological feature of PE, may mediate this association, through direct exposure of the foetal brain to higher levels of inflammatory cytokines; to the various physiological ramifications of maternal immune activation (MIA), which has been strongly implicated in neurodevelopmental and psychiatric disorders; and through perpetuation of the angiogenic factor imbalance and exaggerated oxidative stress seen in PE. Through these various mechanisms, inflammation may adversely affect neuronal development, altering the developmental trajectory of the brain. Methods: Chapter 2 investigated the effects of maternal serum from women with PE or a healthy uncomplicated pregnancy on neurite growth and mitochondrial function in neuronally differentiated human SH-SY5Y neuroblastoma cells. Following this, the pleiotropic cytokine IL-6, was investigated as a potential mechanism. IL-6 concentration was measured in maternal sera and placentae; IL_6 signalling was explored in serum-treated cells; neurite growth was investigated while inhibiting IL-6; and. Lastly, cells were treated with recombinant IL-6 alone. Chapter 3 examined the effects of the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE, on neuronal development. The human neural progenitor cell (NPC) line ReNcell® VM was differentiated into a mixed culture of post-mitotic neurons and glia, and exposed to sFlt-1 during development. The effects of sFlt-1 on neurite length, and βIII tubulin mRNA and protein expression was measured. Lastly, VEGFA inhibition was explored as a potential mechanism by co-treating cells with VEGFA and sFlt-1. Chapter 4 examined the association between maternal C-reactive protein (CRP; as a surrogate measure of MIA) on offspring brain development through analysis of human neuroimaging data from the FinnBrain birth cohort study. We studied the association between maternal prenatal CRP and offspring cortical thickness, surface area, and volume, using vertex-wise statistics; white matter fractional anisotropy (FA) and mean diffusivity (MD), using voxel-wise statistics; and neuronal differentiation and morphology in vitro by exposing developing human neurons to low- or high-CRP maternal serum. Chapter 5 explored the relationship between immune system activity and brain structure in typically developing 5-year-old children. This study employed very similar methods as those in Chapter 4, and was also set within FinnBrain. This chapter examined the association between CRP and cerebrocortical thickness surface area, and volume; white matter FA and MD; and neuronal differentiation and morphology. Results: Chapter 2 - Cells exposed to PE serum for 72h exhibited increased neurite growth and mitochondrial respiration compared to controls. IL-6 was elevated in maternal PE sera, and SH-SY5Y cells exposed to PE serum for 24h had increased phospho-STAT3 levels, which is a key intracellular mediator of IL-6 signalling. Furthermore, incubation with an anti-IL-6 neutralizing antibody prevented the effects of PE serum on neurite growth, while treatment with IL-6 promoted neurite growth in SH-SY5Y cells. Collectively, these data show elevated serum levels of maternal IL-6 in PE, which increases neurite growth and mitochondrial function in SH-SY5Y cells. Chapter 3 - sFlt-1 induced a significant reduction in neurite growth up to a concentration of 100 ng/mL. sFlt-1 (100 ng/mL) also reduced βIII-tubulin mRNA and neuronal differentiation of neurospheres. These effects are thought to be elicited by inhibition of endogenous autocrine and paracrine VEGFA signalling undifferentiated NPCs and post-mitotic neurons/glia expressed VEGFA and its receptor VEGFR-2, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Taken together, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, independent of its previously characterised role in blood vessel formation. Chapter 4 - Maternal CRP within a normal physiological range (< 10 mg/L) was associated with cortical volume in one cluster of the right lingual gyrus in 5-year-old males, and increased white matter FA, and reduced MD, in 5-year-old females. Hyperphysiological maternal CRP (> 10 mg/L), was associated with increased surface area or volume in three clusters of the cortex in 5-year-old females, and increased FA and decreased MD in female infants, particularly in the left external capsule and body of corpus callosum. In line with these neuroimaging findings, high-CRP maternal serum increased neurite growth of human neurons in vitro, particularly from mothers with female offspring. Overall, these data show that maternal CRP is associated with sex-specific cerebrocortical and white matter alterations in typically developing children. Chapter 5 - CRP was associated with increased cortical surface area or volume in distinct, and sex-specific clusters of the cerebral cortex. Serum from children with elevated CRP increased neurite growth and growth cone surface area in human neurons, the latter effect caused by female sera only. Overall, these findings demonstrate that immune activation in 5-year-old children is associated with brain structural parameters in vivo and neuronal development in vitro, with effects differing by biological sex. Conclusions: These data provide converging evidence for both direct and indirect actions of immune mediators on neuronal development at the single cell level, and sex-specific associations between both MIA and childhood immune activation on human brain development. Collectively, they elucidate a mechanistic role for inflammatory mediators in human neuronal and brain development, particularly in the context of pre-eclampsia.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBarron, A. 2024. Pre-eclampsia and neuronal development: the potential pathogenic role of inflammation. PhD Thesis, University College Cork.
dc.identifier.endpage208
dc.identifier.urihttps://hdl.handle.net/10468/16443
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectIrish Research Council for Science, Engineering and Technology (Grant no. R18952)
dc.rights© 2024, Aaron Barron.
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectPre-eclampsia
dc.subjectNeurodevelopment
dc.subjectInflammation
dc.subjectImmune
dc.subjectNeuron
dc.titlePre-eclampsia and neuronal development: the potential pathogenic role of inflammation
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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