IL-6 - A KEY MECHANISTIC PLAYER LINKING PRENATAL EARLY-LIFE STRESS AND CHILDHOOD NEURODEVELOPMENTAL OUTCOMES?

Exposure to early-life stress (ELS) is a risk factor for neurodevelopmental disorders (NDDs). We hypothesise ELS induces ongoing dysregulation of immune pathways, specifically IL-6 signalling, resulting in altered brain development/function. Here, we aimed to investigate the link between ELS, IL-6 signalling and NDDs across rodent and human paradigms.
Wistar rats were exposed to the viral mimetic, poly(I:C), in utero to induce prenatal ELS. Offspring anxiety/cognitive behaviours were assessed and developmental (21d, 35d, 100d) brains/plasma collected to quantify IL-6 protein. Human participants (N=240) were from the Wirral Child Health and Development Study, a longitudinal birth cohort. We utilised prenatal (32wk) and postnatal (2.5yr) maternal depression (Edinburgh Depression Scale) exposure as ELS measures. 3.5yr child externalising/internalising behaviours were assessed by CBCL and child salivary IL-6 DNA methylation was developmentally (1yr, 2.5yr, 3.5yr) measured. Results were analysed using general linear mixed modelling accounting for experimental confounders, including sex.
In rats, poly(I:C)-exposed offspring displayed a cognitive deficit with an increased interdimensional/extradimensional shift in the attentional set-shifting task, alongside heightened anxiety behaviours. 21-100d brain/plasma IL-6 was elevated in exposed offspring and positively associated with 100d cognitive deficits. In humans, exposure to either prenatal or postnatal maternal depression associated with increased 3.5yr child externalising behaviours. Exposure to higher prenatal maternal depression associated with reduced IL-6 methylation (indicative of increased IL-6 expression) from age 2.5yr. Accordingly, from 2.5yr, child IL-6 methylation had an inverse association with 3.5yr child externalising behaviours. Together, results indicate prenatal ELS exposure associates with offspring IL-6 dysregulation and NDD behaviours, across species/stress paradigms.