Dysregulated gene expression associated with inflammatory and translation pathways in activated monocytes from children with autism spectrum disorder.
Dysregulated gene expression associated with inflammatory and translation pathways in activated monocytes from children with autism spectrum disorder.
复制标题
DOI：
10.1038/s41398-021-01766-0
复制
发表时间：
2022-01-26
影响因子：
6.8
通讯作者：
Ashwood P
中科院分区：
文献类型：
--
作者：
Hughes HK;Rowland ME;Onore CE;Rogers S;Ciernia AV;Ashwood P
自闭症谱系障碍(ASD)是一种复杂的发育障碍，其特征是社交、交流和刻板印象行为方面的缺陷。免疫功能障碍是ASD常见的并存疾病，先天免疫激活见于大脑和外周。我们先前发现，外周血单核细胞在脂磷壁酸和脂多糖刺激下的细胞因子反应有显著差异，这两种物质分别激活Toll样受体−2和4。然而，对单核细胞基因表达对这些刺激剂的反应还没有进行无偏见的检查。为了确定TLR激活对ASD单核细胞基因表达的影响，我们分离了26例诊断为自闭症(AD)或广泛性发育障碍(PDDNOS)的儿童和22例典型发育期(TD)儿童的外周血单核细胞，并将其与LTA或脂多糖共同培养24 h，然后进行测序。TLR2和TLR4的激活都诱导了免疫基因的表达，与TD样本相比，AD患者中有一个亚群受到不同的调控。作为对内毒素的反应，AD儿童的单核细胞显示出独特的KEGG途径和GO术语的增加，其中包括关键的免疫调节基因。相比之下，TD儿童的单核细胞对TLR刺激的反应显示与翻译相关的基因表达持续下降。在AD或PDDNOS单核细胞中没有观察到这种下降，这表明ASD儿童单核细胞未能适当下调延长的免疫反应。由于单核细胞参与免疫反应的早期协调，我们的发现将有助于阐明ASD免疫功能障碍的调节机制。
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by deficits in social interactions, communication, and stereotypical behaviors. Immune dysfunction is a common co-morbidity seen in ASD, with innate immune activation seen both in the brain and periphery. We previously identified significant differences in peripheral monocyte cytokine responses after stimulation with lipoteichoic acid (LTA) and lipopolysaccharide (LPS), which activate toll-like receptors (TLR)−2 and 4 respectively. However, an unbiased examination of monocyte gene expression in response to these stimulants had not yet been performed. To identify how TLR activation impacts gene expression in ASD monocytes, we isolated peripheral blood monocytes from 26 children diagnosed with autistic disorder (AD) or pervasive developmental disorder—not otherwise specified (PDDNOS) and 22 typically developing (TD) children and cultured them with LTA or LPS for 24 h, then performed RNA sequencing. Activation of both TLR2 and TLR4 induced expression of immune genes, with a subset that were differentially regulated in AD compared to TD samples. In response to LPS, monocytes from AD children showed a unique increase in KEGG pathways and GO terms that include key immune regulator genes. In contrast, monocytes from TD children showed a consistent decrease in expression of genes associated with translation in response to TLR stimulation. This decrease was not observed in AD or PDDNOS monocytes, suggesting a failure to properly downregulate a prolonged immune response in monocytes from children with ASD. As monocytes are involved in early orchestration of the immune response, our findings will help elucidate the mechanisms regulating immune dysfunction in ASD.
登录
查看更多内容
影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
25
作者：
Gazestani, Vahid H.;Pramparo, Tiziano;Lewis, Nathan E.
通讯作者：
Lewis, Nathan E.
自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
影响因子：
15.1
作者：
Enstrom, Amanda M.;Onore, Charity E.;de Water, Judy A. Van;Ashwood, Paul
通讯作者：
Ashwood, Paul