A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.

中文翻译：

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自闭症谱系障碍患者的粒细胞巨噬细胞集落刺激因子诱导的巨噬细胞通过分泌促炎细胞因子对神经元树突产生不利影响

越来越多的证据表明，周围组织以及中枢神经系统的免疫功能障碍和炎症与自闭症谱系障碍 (ASD) 中观察到的神经发育缺陷有关。据报道，自闭症谱系障碍患者的血浆、血清和外周血单核细胞中促炎细胞因子的表达升高。这些细胞因子的表达水平与 ASD 行为障碍和症状的严重程度相关。在之前的研究中，我们课题组报道了粒细胞-巨噬细胞集落刺激因子诱导的巨噬细胞（GM-CSF MΦ）中肿瘤坏死因子-α（TNF-α）的表达以及GM-CSF MΦ/中TNF-α的表达比率自闭症谱系障碍 (ASD) 个体中的 M-CSF MΦ（巨噬细胞集落刺激因子诱导的巨噬细胞）明显高于典型发育 (TD) 个体。然而，巨噬细胞和高表达的细胞因子如何影响神经元的机制仍有待解决。为了阐明巨噬细胞对人类神经元的影响，我们使用了一个共培养系统，该系统由对照人诱导多能干细胞衍生的神经元和从 5 名 TD 个体和 5 名 ASD 个体的外周血单核细胞中获得的分化巨噬细胞组成。所有参与者都是男性和日本人。我们的共培养实验结果表明，GM-CSF MΦ 通过分泌促炎细胞因子、白介素-1α 和 TNF-α 影响神经元的树突生长。来自 ASD 个体的巨噬细胞比来自 TD 个体的巨噬细胞产生更严重的影响。我们研究的主要局限性是样本量小，性别偏向男性，使用人工极化的巨噬细胞，以及无法直接观察同一个体的神经元和巨噬细胞之间的相互作用。我们的共培养系统揭示了 ASD 个体中 GM-CSF MΦ 对神经元的非细胞自主不利影响，这是由 IL-1α 和 TNF-α 介导的。这些结果可能支持 ASD 的免疫功能障碍假说，为其病理学提供新的见解。