JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis
JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis
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DOI：
10.1111/jpi.12323
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发表时间：
2016-05
影响因子：
10.3
通讯作者：
Hui-Mei Wu;Q. Shen;L. Fang;Shi-Hai Zhang;Peiming Shen;Ya-Jing Liu;Rong-Yu Liu
中科院分区：
文献类型：
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作者：
Hui-Mei Wu;Q. Shen;L. Fang;Shi-Hai Zhang;Peiming Shen;Ya-Jing Liu;Rong-Yu Liu
Toll样受体（TLR）在哮喘等过敏性气道疾病的发病机制中起关键作用。TLR 9是作为治疗哮喘的方法而被最广泛研究的TLR之一。本研究旨在探讨TLR 9在过敏性气道炎症中的作用及其机制。野生型（WT）小鼠和TLR 9 −/−小鼠用OVA致敏和激发以建立过敏性气道疾病模型。我们发现，TLR 9的表达伴随着OVA激发后的气道炎症而升高，TLR 9缺乏有效抑制气道炎症，包括血清OVA特异性免疫球蛋白E（IgE）、肺部炎症细胞募集、粘液分泌和支气管肺泡灌洗液（BALF）炎症细胞因子产生。同时，在OVA攻击的WT小鼠中，肺组织中羟基吲哚o甲基转移酶（HIOMT）的蛋白表达、血清中褪黑激素水平和BALF中的褪黑激素水平降低，而这些降低通过TLR 9缺陷显著恢复。此外，我们发现，尽管TLR 9缺乏对OVA诱导的JNK磷酸化没有影响，但特异性抑制剂SP 600125抑制JNK可显著降低OVA诱导的TLR 9表达，表明JNK是TLR 9的上游信号分子。此外，SP 600125治疗促进了OVA激发的WT小鼠中过敏性气道炎症的消退，但没有进一步改善OVA激发的TLR 9 −/−小鼠中的过敏性气道炎症。类似地，SP 600125显著恢复了OVA攻击的WT小鼠中HIOMT的蛋白表达和褪黑激素的水平，而TLR 9缺乏没有进一步增强这种效果。总之，我们的结果表明JNK-TLR 9信号通路通过抑制褪黑素的生物合成介导过敏性气道炎症。
Toll‐like receptors (TLRs) play pivotal role in the pathogenesis of allergic airway diseases such as asthma. TLR9 is one of the most extensively studied TLRs as an approach to treat asthma. In this study, we investigated the role of TLR9 in the allergic airway inflammation and the underlying mechanism. Wild‐type (WT) mice and TLR9−/− mice were sensitized and challenged with OVA to establish allergic airway disease model. We found that the expression of TLR9 was elevated concomitantly with airway inflammation post‐OVA challenge, and TLR9 deficiency effectively inhibited airway inflammation, including serum OVA‐specific immunoglobulin E (IgE), pulmonary inflammatory cell recruitment, mucus secretion, and bronchoalveolar lavage fluid (BALF) inflammatory cytokine production. Meanwhile, the protein expression of hydroxyindole‐o‐methyltransferase (HIOMT) in lung tissues, the level of melatonin in serum, and BALF were reduced in OVA‐challenged WT mice, while these reductions were significantly restored by TLR9 deficiency. Additionally, we showed that although TLR9 deficiency had no effect on OVA‐induced phosphorylation of JNK, inhibition of JNK by specific inhibitor SP600125 significantly decreased OVA‐induced expression of TLR9, suggesting that JNK is the upstream signal molecular of TLR9. Furthermore, SP600125 treatment promoted resolution of allergic airway inflammation in OVA‐challenged WT mice, but not further ameliorated allergic airway inflammation in OVA‐challenged TLR9−/− mice. Similarly, SP600125 significantly restored the protein expression of HIOMT and the level of melatonin in OVA‐challenged WT mice, while such effect was not further enhanced by TLR9 deficiency. Collectively, our results indicated that JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis.