The role of interleukin IL-17a in the induction of reactive astrocytes derived from individuals with autism spectrum disorder

Abstract

Maternal immune activation (MIA) has emerged as an important environmental risk factor for Autism Spectrum Disorder (ASD). Animal models of MIA have suggested that after an infection and immune activation during pregnancy, maternal proinflammatory cytokines can cross the placenta and impact fetal brain development. Among them, interleukin 17a (IL-17a) has been shown to play an etiological role in the brain cytoarchitecture and ASD-like behavior abnormalities observed in the MIA offspring. The cellular targets of IL-17a in the developing human brain are still not fully understood, and one possible mechanism by which IL-17a may contribute to ASD is via induction of astrocyte reactivity. However, the action of IL-17a on astrocytic reactivity and whether this IL-17a-induced immune response is deregulated in individuals with ASD is still not well understood. This research project aims to verify whether IL-17a induces the reactivity of astrocytes derived from induced pluripotent stem cells (iPSCs) of individuals with ASD and control individuals, whether this response to IL-17a is different between both groups, and whether IL-17a induces astrocyte reactivity in brain organoids derived from iPSCs. To this end, astrocytes cultured in monolayer and brain organoids derived from iPSCs of individuals with ASD and controls will be used as experimental models, and will be analyzed in astrocytes treated with IL17a: the nuclear translocation of the transcription factor NF-kB, the expression of markers of reactive astrocytes and pro-inflammatory molecules, the morphology, proliferation and reuptake of the neurotransmitter glutamate.