Gomes Ana Karolyne Santos, Dantas Rafaelly Mayara, Yokota Bruno Yukio, Silva André Luiz Teles E, Griesi-Oliveira Karina, Passos-Bueno Maria Rita, Sertié Andréa Laurato
Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo, Brazil.
Centro de Estudos do Genoma Humano e Células Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
Front Neurosci. 2022 Mar 14;16:828646. doi: 10.3389/fnins.2022.828646. eCollection 2022.
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.
产前暴露于母体免疫激活（MIA）被认为会增加自闭症谱系障碍（ASD）的发生概率。动物研究的最新证据表明，白细胞介素-17a（IL-17a）在促进MIA诱导的行为和大脑异常方面起着关键作用，这些异常类似于ASD。然而，IL-17a如何作用于人类发育中的大脑以及直接受IL-17a信号影响的细胞类型仍不清楚。在本研究中，我们使用了来自已知和未知遗传病因的ASD个体以及神经典型对照的诱导多能干细胞衍生的神经祖细胞（NPC），以研究外源性IL-17a对NPC增殖、迁移和神经元分化的影响，以及IL-17a与ASD的遗传风险因素是否相互作用加剧NPC功能的改变。我们观察到，ASD和对照NPC内源性表达IL-17a受体（IL17RA），并且IL-17a/IL17RA激活调节下游ERK1/2和mTORC1信号通路。外源性IL-17a并未诱导ASD和对照NPC的异常增殖和迁移，但另一方面，它显著增加了这些细胞中突触（突触素-1、突触结合蛋白-1）和神经元极性（微管相关蛋白2）蛋白的表达。此外，由于我们观察到ASD和对照NPC对外源性IL-17a表现出相似的反应，因此可能需要一个除IL-17a之外还包含其他免疫分子的更具炎症性的环境，以在神经发育过程中触发基因-环境相互作用。总之，我们的结果表明，外源性IL-17a正向调节人类NPC的神经元分化，这可能会干扰正常的神经元和突触发育，并导致与MIA相关的脑功能和行为变化。
