Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment
Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment
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DOI：
10.1016/j.immuni.2016.04.005
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发表时间：
2016-04-19
期刊：
影响因子：
32.4
通讯作者：
Prinz, Marco
中科院分区：
文献类型：
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作者：
Blank, Thomas;Detje, Claudia N.;Prinz, Marco
在接受I型干扰素（ifn）治疗的病毒感染的恶性肿瘤患者和自身免疫性疾病患者中，疾病行为和认知功能障碍经常以未知的机制发生。我们发现，在疾病行为中，单链RNA病毒、双链RNA配体和IFN共享涉及黑色素瘤分化相关蛋白5 （MDA5）、视黄酸诱导基因1 （RIG-I）和线粒体抗病毒信号蛋白（MAVS）的通路，并随后在小鼠脑内皮和上皮中特异性诱导IFN反应。行为改变特异性依赖于脑内皮和上皮IFN受体链1 （IFNAR）。通过基因分析，我们发现内皮来源的趋化因子配体CXCL10通过突触可塑性损伤介导行为改变。这些结果确定了脑内皮细胞和上皮细胞是病毒引起的疾病行为的天然看门人，证明了组织特异性IFNAR参与，并建立了CXCL10-CXCR3轴作为治疗病毒感染和I型IFN治疗期间行为改变的靶标。
Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.