Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation
Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation
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DOI：
10.1016/j.cell.2018.12.012
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发表时间：
2019-01-24
期刊：
影响因子：
64.5
通讯作者：
Quintana, Francisco J.
中科院分区：
文献类型：
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作者：
Wheeler, Michael A.;Jaronen, Merja;Quintana, Francisco J.
全基因组研究已经确定了与神经系统疾病相关的遗传变异。环境因素也发挥着重要作用，但目前尚无对其进行综合研究的方法。我们开发了一种方法，结合基因组数据、新型斑马鱼模型筛选、计算模型、扰动研究和多发性硬化症 (MS) 患者样本，以评估环境暴露对中枢神经系统炎症的影响。我们发现除草剂利谷隆通过激活 sigma 受体 1、肌醇需求酶 1 α (IRE1 α) 和 X-box 结合蛋白 1 (XBP1) 信号传导来增强星形胶质细胞促炎活性。事实上，星形胶质细胞特异性 shRNA 和 CRISPR/Cas9 驱动的基因失活与 RNA-seq、ATAC-seq、ChIP-seq 和患者样本研究相结合表明，IRE1 alpha-XBP1 信号传导可促进实验性自身免疫性脑脊髓炎 (EAE) 以及可能的 MS 中的中枢神经系统炎症。总之，这些研究定义了控制星形胶质细胞致病活动的环境机制，并建立了多学科方法来系统研究环境暴露对神经系统疾病的影响。
Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1 alpha (IRE1 alpha), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1 alpha-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.