Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor.
Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor.
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DOI：
10.1038/nm.4106
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发表时间：
2016-06
期刊：
影响因子：
82.9
通讯作者：
Quintana FJ
中科院分区：
文献类型：
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作者：
Rothhammer V;Mascanfroni ID;Bunse L;Takenaka MC;Kenison JE;Mayo L;Chao CC;Patel B;Yan R;Blain M;Alvarez JI;Kébir H;Anandasabapathy N;Izquierdo G;Jung S;Obholzer N;Pochet N;Clish CB;Prinz M;Prat A;Antel J;Quintana FJ
星形胶质细胞在中枢神经系统（CNS）中起着重要的作用，在健康和疾病。通过全基因组分析，我们检测到的转录反应，I型干扰素（IFN-I）在星形胶质细胞在实验性中枢神经系统自身免疫，也在中枢神经系统病变多发性硬化症（MS）患者。星形胶质细胞中的IFN-I信号传导通过配体激活的转录因子芳烃受体（AhR）和细胞因子信号传导抑制因子2（SOCS 2）降低炎症和实验性自身免疫性脑脊髓炎（EAE）疾病评分。鼻内给药IFN-β的抗炎作用部分由AhR介导。饮食中的色氨酸被肠道微生物群代谢成AhR激动剂，作用于星形胶质细胞以限制中枢神经系统炎症。在恢复期，氨苄青霉素治疗后EAE评分增加，并且通过补充色氨酸代谢物吲哚、吲哚-3-硫酸酯（I3 S）、吲哚-3-丙酸（IPA）和吲哚-3-醛（IAld）或细菌酶葡聚糖酶，在氨苄青霉素治疗的小鼠中CNS炎症减少。在MS患者中，AhR激动剂的循环水平降低。这些发现表明，在CNS中产生的IFN-1与肠道植物群从饮食色氨酸衍生的代谢物组合起作用，以激活星形胶质细胞中的AhR信号传导并抑制CNS炎症。
Astrocytes play important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-I) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from multiple sclerosis (MS) patients. IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) and suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered IFN-β are partly mediated by AhR. Dietary tryptophan is metabolized by the gut microbiota into AhR agonists that act on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AhR agonists were decreased. These findings suggest that IFN-I produced in the CNS act in combination with metabolites derived from dietary tryptophan by the gut flora to activate AhR signaling in astrocytes and suppress CNS inflammation.