Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism
Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism
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Tyrphostin AG126 通过双重机制在中枢神经系统炎症中发挥神经保护作用
作者：
Menzfeld C;John M;van Rossum D;Regen T;Scheffel J;Janova H;Götz A;Ribes S;Borisch A;Boutin P;Neumann K;Bremes V;Wienands J;Reichardt H.M;Lühder F;Tischner D;Waetzig V;Herdegen T;Teismann P;Greig I;Müller M.
推定的蛋白酪氨酸激酶 (PTK) 抑制剂酪氨酸磷酸化蛋白 AG126 已被证明对各种炎症性疾病模型有益。然而分子靶点和细胞机制仍然是个谜。我们在此证明 AG126 治疗对实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症模型）具有有益作用。 AG126 可缓解临床症状，减少致脑炎 Th17 分化，减少炎症性中枢神经系统浸润以及小胶质细胞激活，并减轻髓磷脂损伤。我们发现 AG126 直接抑制布鲁顿酪氨酸激酶 (BTK)，这是一种与 B 细胞受体和 Toll 样受体 (TLR) 信号传导相关的 PTK。然而，BTK 抑制不能解释整个活性谱。对小胶质细胞中 TLR 诱导的促炎细胞因子表达的影响涉及 AG126 水解及其二腈侧链向丙二腈 (MN) 的转化。值得注意的是，虽然释放的 MN 随后可以介导关键的 AG126 功能，但 EAE 中的全面保护仍然需要提供完整的 AG126。因此，它的抗炎潜力，尤其是对 TLR 信号传导的干扰，依赖于包含 BTK 和新型 MN 敏感靶点的双重机制。这两个原则对于先天性和适应性免疫功能紊乱的治疗管理具有巨大潜力。 GLIA 2015；63：1083–1099
The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll‐like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR‐induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti‐inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN‐sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. GLIA 2015;63:1083–1099