新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 生物研究 » Nat Med:I型干扰素激活转录因子AHR介导中枢神经系统炎症反应

Nat Med:I型干扰素激活转录因子AHR介导中枢神经系统炎症反应

来源:生物谷 2016-06-12 11:37

20166月12日 讯 /生物谷BIOON/ --星形胶质细胞是中枢神经系统中最丰富的细胞类群,它们参与了多种功能,包括调控血脑屏障、代谢调节、神经信号的传输以及中枢神经系统的损伤修复。在多发性硬化以及脑膜炎疾病发生过程中,星形胶质细胞也有着重要的影响。星形胶质细胞的功能受到脑部内外的多种分子的调节,鉴定出这些关键的分子对于理解星形胶质细胞的功能有着重要的意义。

肠道微生物的代谢产物能够通过多种方式调节免疫反应,不过,这些分子对于中枢神经系统内的免疫反应有何影响目前研究的还很少。针对以上问题,来自哈佛医学院的Francisco J Quintana课题组进行了深入研究,相关结果发表在最近一期的《nature medicine》杂志上。

首先,作者对小鼠进行MOG35–55的注射,诱导其产生脑膜炎。在随后的转录组分析中,作者发现脑膜炎发病小鼠的星形胶质细胞中有1千多种基因的表达发生了变化。通过聚类分析,他们发现其中大部分属于IFN-I诱导产生的基因。

I型干扰素对于炎症反应具有重要的调节作用。作者制备了能够人为敲低IFNR1I型干扰素受体基因)的慢病毒,并将其注射入诱导产生脑膜炎的小鼠脑部。结果显示:IFNR1的下调使得小鼠脑膜炎疾病严重程度上升。

进一步,作者发现IFNR1的下调还会导致免疫调节转录因子aryl hydrocarbon receptorAHR)以及其靶基因Cyp1b1的表达量的下降。与此相符,作者通过体外实验证明IFN的刺激AHR的上调。这些数据表明IFN-I的信号能够提高AHR信号并限制中枢神经系统的炎症反应强度。

之后,作者检测了IFN受体下游的信号激活情况。结果显示,IFN对星形胶质细胞的刺激能够上调AHR基因的表达。

接下来,为了研究AHR的表达是否与中枢神经系统炎症的缓解有关,作者构建了星形胶质细胞特异性AHR敲除小鼠。之后同样进行了脑膜炎的诱导。结果显示,相比对照组小鼠,AHR敲除小鼠的病情更为恶化。为了研究AHR是如何调节炎症反应的,作者进行了染色质免疫共沉淀试验,结果显示,在AHR缺失的情况下,NFKB与下游顺式作用元件的结合能力得到了提升,这说明AHR能够负向调节NFKB的活性。

最后,作者发现肠道微生物通过分解色氨酸可以生成多种AHR的配体物质。这些配体能够介导IFN-I引发的炎症负向调节活性。(生物谷Bioon.com

本文系生物谷原创编译整理,欢迎转载!点击 获取授权 。更多资讯请下载生物谷APP. 

doi:10.1038/nm.4106

PMC:

PMID:

Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor

Veit Rothhammer, Ivan D Mascanfroni, Lukas Bunse, Maisa C Takenaka, Jessica E Kenison, Lior Mayo, Chun-Cheih Chao, Bonny Patel, Raymond Yan, Manon Blain, Jorge I Alvarez, Hania Kébir, Niroshana Anandasabapathy5, Guillermo Izquierdo, Steffen Jung, Nikolaus Obholzer, Nathalie Pochet, Clary B Clish, Marco Prinz, Alexandre Prat, Jack Antel & Francisco J Quintana

Astrocytes have 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-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). 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 the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-b are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect 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, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库