Abstract
Prenatal exposure to maternal immune activation (MIA) has been suggested to increase the probability of autism spectrum disorder (ASD). Recent evidence from animal studies indicates a key role for interleukin-17a (IL-17a) in promoting MIA-induced behavioral and brain abnormalities reminiscent of ASD. However, it is still unclear how IL-17a acts on the human developing brain and the cell types directly affected by IL-17a signaling. In this study, we used iPSC-derived neural progenitor cells (NPCs) from individuals with ASD of known and unknown genetic cause as well as from neurotypical controls to examine the effects of exogenous IL-17a on NPC proliferation, migration and neuronal differentiation, and whether IL-17a and genetic risk factors for ASD interact exacerbating alterations in NPC function. We observed that ASD and control NPCs endogenously express IL-17a receptor (IL17RA), and that IL-17a/IL17RA activation modulates downstream ERK1/2 and mTORC1 signaling pathways. Exogenous IL-17a did not induce abnormal proliferation and migration of ASD and control NPCs but, on the other hand, it significantly increased the expression of synaptic (Synaptophysin-1, Synapsin-1) and neuronal polarity (MAP2) proteins in these cells. Also, as we observed that ASD and control NPCs exhibited similar responses to exogenous IL-17a, it is possible that a more inflammatory environment containing other immune molecules besides IL-17a may be needed to trigger gene-environment interactions during neurodevelopment. In conclusion, our results suggest that exogenous IL-17a positively regulates the neuronal differentiation of human NPCs, which may disturb normal neuronal and synaptic development and contribute to MIA-related changes in brain function and behavior.
Highlights
In addition to strong evidence for the genetic transmission of autism spectrum disorder (ASD), exposure to environmental risk factors during critical periods of brain development can influence risk for ASD
All ASD- and control-derived neural progenitor cells (NPCs) samples have recently been characterized by the expression of typical lineage-specific markers (Nestin, SOX1, and SOX2), as well as the ability to differentiate into neurons and astrocytes (Mansur et al, 2021)
This study aimed to investigate whether IL-17a, a key proinflammatory cytokine associated with maternal immune activation (MIA)-induced cortical and ASD-like behavioral abnormalities, affects human NPC biology and potentially synergizes with genetic risk factors for ASD changing NPC responses
Summary
In addition to strong evidence for the genetic transmission of autism spectrum disorder (ASD), exposure to environmental risk factors during critical periods of brain development can influence risk for ASD. Several epidemiological studies have suggested that exposure of fetuses to maternal infection during pregnancy increases the likelihood of developing ASD (Wilkerson et al, 2002; Atladóttir et al, 2010; Brown et al, 2014; Lee et al, 2015). In support to this notion, animal models have shown that MIA induced experimentally via immunogens (such as poly I:C, a synthetic double-stranded RNA to mimic viral infection) results in offspring with cortical malformations, behavioral symptoms, and immune dysfunctions reminiscent of ASD (Smith et al, 2007; Abrahams and Geschwind, 2010; Hsiao et al, 2012; Malkova et al, 2012; Choi et al, 2016; Lombardo et al, 2018). In humans, abnormal IL17A gene copy number variations (van der Zwaag et al, 2009) and elevated serum levels of IL-17a (Suzuki et al, 2011; AlAyadhi and Mostafa, 2012; Akintunde et al, 2015) were observed in ASD subjects
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