期刊
BRAIN BEHAVIOR AND IMMUNITY
卷 103, 期 -, 页码 97-108出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2022.04.007
关键词
Interleukin-6; Interferon; Maternal immune activation; iPSC; Folic acid
资金
- NIH [MH113858, MH086846, 2015088]
- Mass General Early Brain Development Initiative
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- Harvard Stem Cell Institute grant
- Harvard Brain Science Initiative seed grant
- Jeanne Marie Lee/Osterhaus Family Foundation
- Brain and Behavior Research Foundation NARSAD Young Investigator Award
- [MH120402]
Translational evidence suggests that cytokines involved in maternal immune activation can harm fetal brain and increase the risk of neuropsychiatric disorders. This study differentiated human pluripotent stem cells to cortical neurons and exposed them to interleukin-6 (IL-6) or interferon-gamma (IFN-gamma). The findings show that IL-6 affects gene expression related to extracellular matrix, actin cytoskeleton, and TGF-beta signaling, while IFN-gamma affects genes related to antigen processing, major histocompatibility complex, and endoplasmic reticulum biology. Mitochondrial respiration and dendritic spine density were also influenced by these cytokines, but pre-treatment with folic acid mitigated their effects.
Translational evidence suggests that cytokines involved in maternal immune activation (MIA), such as interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), can cross the placenta, injure fetal brain, and predispose to neuropsychiatric disorders. To elaborate developmental neuronal sequelae of MIA, we differentiated human pluripotent stem cells to cortical neurons over a two-month period, exposing them to IL-6 or IFN-gamma. IL-6 impacted expression of genes regulating extracellular matrix, actin cytoskeleton and TGF-beta signaling while IFN-gamma impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6, but not IFN-gamma, altered mitochondrial respiration while IFN-gamma, but not IL-6, induced reduction in dendritic spine density. Pre-treatment with folic acid, which has known neuroprotective and anti-inflammatory properties, ameliorated IL-6 effects on mitochondrial respiration and IFN-gamma effects on dendritic spine density. These findings suggest distinct mechanisms for how fetal IL-6 and IFN-gamma exposure influence risk for neuropsychiatric disorders, and how folic acid can mitigate such risk.
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