Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway.
Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway.
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DOI：
10.1002/emmm.201000103
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发表时间：
2010-12
影响因子：
11.1
通讯作者：
Harada, Takayuki
中科院分区：
文献类型：
--
作者：
Guo, Xiaoli;Harada, Chikako;Namekata, Kazuhiko;Matsuzawa, Atsushi;Camps, Monsterrat;Ji, Hong;Swinnen, Dominique;Jorand-Lebrun, Catherine;Muzerelle, Mathilde;Vitte, Pierre-Alain;Rueckle, Thomas;Kimura, Atsuko;Kohyama, Kuniko;Matsumoto, Yoh;Ichijo, Hidenori;Harada, Takayuki
凋亡信号调节激酶1（Apoptosis signal-regulating kinase 1，ASK 1）是一种进化上保守的丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）激酶，在应激和免疫应答中发挥重要作用。在这里，我们表明，ASK 1缺陷减弱实验性自身免疫性脑脊髓炎（EAE）的神经炎症，而不影响T细胞的增殖能力。此外，我们发现EAE上调活化的星形胶质细胞和小胶质细胞中Toll样受体（TLR）的表达，并且TLR可以与ASK 1-p38 MAPK信号传导协同从星形胶质细胞释放关键趋化因子。因此，口服ASK 1特异性小分子量抑制剂可抑制脊髓和视神经中EAE诱导的自身免疫性炎症。这些结果表明，胶质细胞中的TLR-ASK 1-p38通路可以作为包括多发性硬化症在内的自身免疫性脱髓鞘疾病的有效治疗靶点。
Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.
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