Interleukin-6 and Interferon-y Show Different Deleterious Effects in Human Stem Cell-Based Model of Neurodevelopment

Maternal viral and bacterial infections during pregnancy predispose the child to a range of neuropsychiatric disorders later in life. However, relatively few pathogens cross the placenta and harm the fetus directly. A hypothesis has arisen that the maternal immune response to the infections confers the increased risk for neuropsychiatric disorders in the offspring.

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Two pro-inflammatory cytokines, interleukin-6 (IL-6) and interferon-γ (IFN-γ), cross the placenta to aid in normal fetal development and are also key elements of maternal immune activation. Considerable evidence implies they can affect the developing fetal brain and predispose a child to neuropsychiatric disorders.

Researchers at Massachusetts General Hospital have uncovered several mechanisms that mediate these effects, with distinct mechanisms and effects from IL-6 and IFN-γ. In Brain, Behavior, and Immunity, they also report data suggesting folic acid can mitigate the risk.

The authors are Annie Kathuria, PhD, a research fellow in the Center for Genomic Medicine, Kara Lopez-Lengowski, a research technician in the Center for Genomic Medicine, Joshua L. Roffman, MD, MMSc, director of the Mass General Early Brain Development Initiative, Rakesh Karmacharya, MD, PhD, associate professor in the Center for Genomic Medicine.

Methods

The researchers generated induced pluripotent stem cell lines from two healthy humans, one male, and one female. They differentiated them into cortical pyramidal neurons over a two-month period, exposing them to IL-6 or IFN-γ during a critical neurodevelopmental period.

Key Results of Cytokine Exposure

Human cortical neurons that had been exposed to IL-6 during development showed:

• Upregulation in the expression of genes related to chemokine receptor binding and Toll-like receptor signaling
• Downregulation of genes related to an extracellular matrix organization, contractile fibers, the actin cytoskeleton, PI3K–Akt signaling, and TGF-β signaling
• Significant mitochondrial dysfunction (greater metabolism and energy demands)

Human cortical neurons exposed to IFN-γ during development showed:

• Upregulation of genes related to the cellular response to interferons, the adaptive immune response, the major histocompatibility complex, and endoplasmic reticulum function
• Significant reduction in dendritic spine density

Effects of Folic Acid

Folic acid is anti-inflammatory and has neuroprotective effects during fetal development. The research team examined human cortical neurons exposed to folic acid during early differentiation:

• Folic acid alone did not affect gene expression profiles significantly in differentiating neurons
• Folic acid, when pretreated in the context of IL-6 or IFN-γ exposure, led to significant differences in gene expression, and also mitigated the effects of IL-6 on mitochondrial function and the effect of IFN-γ on dendritic spine density

Clinical Relevance

A retrospective cohort study conducted at Mass General, reported in JAMA Psychiatry, suggests that increased gestational exposure to folic acid through food fortification protects the child against cortical thinning and psychosis-spectrum symptoms.

The current study indicates exogenous folic acid may be beneficial because it protects against the deleterious effects of IL-6 and IFN-γ. With implications for preventive interventions, the findings also point to specific cellular processes where folic acid may be protective.

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