Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS.
Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS.
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Laquinimod在星形胶质细胞中的芳基烃受体激活可以改善中枢神经系统的自身免疫性炎症。
DOI：
10.1212/nxi.0000000000000946
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发表时间：
2021-03-04
期刊：
影响因子：
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通讯作者：
Quintana FJ
中科院分区：
文献类型：
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作者：
Rothhammer V;Kenison JE;Li Z;Tjon E;Takenaka MC;Chao CC;Alves de Lima K;Borucki DM;Kaye J;Quintana FJ
多发性硬化症是一种中枢神经系统自身免疫性脱髓鞘疾病，在年轻人中引起神经功能缺陷并导致进行性残疾。芳烃受体（AHR）是一种配体激活的转录因子，可以驱动外周免疫细胞和中枢驻扎细胞的抗炎功能。拉喹莫德是一种为治疗多发性硬化症而开发的药物，已知可激活AHR，但拉喹莫德的细胞靶点仍不完全清楚。在这项工作中，我们分析了星形胶质细胞中AHR激活对其在实验性自身免疫性脑脊髓炎（EAE） ms临床前模型中的有益作用。我们使用条件敲除小鼠，结合RNA-seq基因全基因组表达分析和体外培养系统来研究拉喹莫德对星形胶质细胞的影响。我们发现，拉喹莫德激活星形胶质细胞AHR可改善EAE，这是ms的临床前模型。全基因组RNA-seq转录分析检测了拉喹莫德在EAE过程中对胶质细胞的抗炎作用。此外，我们发现拉喹莫德的Delaq代谢物可以抑制促炎介质的产生，同时激活神经胶质细胞的组织保护机制。综上所述，这些发现表明，临床相关的AHR激动剂激活AHR可能代表了一种治疗MS的新方法。
MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS. We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes. We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia. Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.