Combined inhibition of angiotensin II type 1 receptor and ASK1 significantly attenuates autoimmune optic neuritis
Combined inhibition of angiotensin II type 1 receptor and ASK1 significantly attenuates autoimmune optic neuritis
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发表时间：
2014-04
影响因子：
4.4
通讯作者：
Xiaoli Guo;K. Namekata;C. Harada;T. Harada
中科院分区：
文献类型：
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作者：
Xiaoli Guo;K. Namekata;C. Harada;T. Harada
程序编号：5769海报板编号：B 0105演示时间：8：30 AM-10：15 AM联合抑制血管紧张素II 1型受体和ASK 1显着减弱自身免疫性视神经炎Xiaoli Guo，Kazuhiko Namekata，Chikako Harada，Takayuki Harada.东京都立医学科学研究所，日本东京。目的：研究联合抑制血管紧张素II 1型受体（AT 1 R）和凋亡信号调节激酶1（ASK 1）（一种丝裂原活化蛋白激酶（MAP 3 K））对多发性硬化（MS）动物模型实验性自身免疫性脑脊髓炎（EAE）小鼠视神经炎的影响。方法：我们在雌性野生型和ASK 1缺陷型小鼠中诱导EAE。血管紧张素II（AngII），肾素-血管紧张素系统（RAS）的主要效应分子，和Toll样受体（TLR）信号转导对EAE的影响进行了检查。每天对临床体征进行评分，并通过多焦视网膜电图评估视功能。对脊髓和视神经进行组织学分析。原代培养星形胶质细胞和骨髓来源的树突状细胞（DC）被用来阐明血管紧张素II和TLR表达之间的关系。结果如下：我们证实AngII在EAE早期表达增加，AngII通过NF-κB途径诱导星形胶质细胞和DC中TLR 4的表达。由于我们先前证明了ASK 1与TLR 4结合并调节先天免疫应答，因此我们研究了RAS和ASK 1信号传导之间可能的相互作用。联合应用AT 1 R拮抗剂、NFκB核转位抑制剂和ASK 1抑制剂可抑制星形胶质细胞和DC的趋化因子产生，降低DC的抗原提呈能力和T细胞增殖。与这些发现相一致，在体内给予AT 1 R拮抗剂ASK 1缺陷小鼠显著降低了EAE的发生率，并减弱了脊髓和视神经的脱髓鞘、视网膜神经节细胞死亡和视力损害。结论：我们的研究结果表明，神经细胞和免疫细胞中的RAS-NF-κ BTLR 4-ASK 1通路是治疗视神经炎的有效靶点。治疗高血压的处方药可用于预防和治疗神经炎性疾病。商业关系：郭晓丽，无;名形和彦，无;原田千香子，无;原田孝之，无支持：日本文部科学省资助
Program Number: 5769 Poster Board Number: B0105 Presentation Time: 8:30 AM–10:15 AM Combined inhibition of angiotensin II type 1 receptor and ASK1 significantly attenuates autoimmune optic neuritis Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada. Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Purpose: To study the effects of combined inhibition of angiotensin II type 1 receptor (AT1R) and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase (MAP3K), on optic neuritis in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Methods: We induced EAE in female wild-type and ASK1-deficient mice. The effects of angiotensin II (AngII), the principal effector molecule of the renin-angiotensin system (RAS), and Toll-like receptor (TLR) signaling on EAE were examined. Clinical signs were scored daily and visual function was assessed by multifocal electroretinograms. Histopathological analysis of spinal cords and optic nerves was performed. Primary cultured astrocytes and bone marrow-derived dendritic cells (DC) were used to elucidate the relationship between AngII and TLR expression. Results: We demonstrated that AngII expression is increased in the early phase of EAE and AngII induces TLR4 expression via an NF-κB pathway in astrocytes and DCs. Since we previously demonstrated that ASK1 binds to TLR4 and regulates innate immune responses, we examined possible interactions between the RAS and ASK1 signaling. Combined application of an AT1R antagonist, NFκB nuclear translocation inhibitor and ASK1 inhibitor suppressed chemokine productions in astrocytes and DCs, reduced antigenpresentation capability of DCs and T cell proliferation. Consistent with these findings, in vivo administration of an AT1R antagonist to ASK1-deficient mice significantly reduced the incidence of EAE, and attenuated demyelination in spinal cords and optic nerves, retinal ganglion cell death and visual impairment. Conclusions: Our findings suggest a novel pathway of RAS-NF-κBTLR4-ASK1 in neural and immune cells as a valid therapeutic target for optic neuritis. Prescribed drugs to treat high blood pressure may be available for the prevention and treatment for neuroinflammatory diseases. Commercial Relationships: Xiaoli Guo, None; Kazuhiko Namekata, None; Chikako Harada, None; Takayuki Harada, None Support: Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan