Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88
Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88
复制标题
穿心莲内酯通过诱导 MyD88 的自噬蛋白水解来减轻咪喹莫特诱导的小鼠牛皮癣。
DOI：
10.1016/j.bcp.2016.06.001
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发表时间：
2016-09-01
影响因子：
5.8
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Shao, Fenli;Tan, Tao;Xu, Qiang
银屑病是一种慢性炎症性皮肤病，Toll样受体过度激活，在银屑病的发生发展中起重要作用。靶向TLR信号仍然是治疗银屑病的一个挑战。在这里，我们发现小分子天然产物穿心莲内酯(Andro)通过减少皮肤中IL-23和IL-1β的表达来缓解咪喹莫特-但不能减轻IL-23(IL-23)诱导的小鼠银屑病。在微管相关蛋白1轻链3β(MAPILC3B)基因敲除的小鼠中，Andro对咪喹莫特诱导的银屑病没有改善作用。此外，Andro以MAP1LC3B依赖的方式抑制脂多糖(LPS)处理的骨髓来源的树突状细胞(BMDCs)中IL-23、IL-6和IL-1β的mRNA表达，但不抑制CD80和CD86的表达。此外，Andro还抑制咪喹莫特诱导的小鼠BMDCs中IL-23、IL-6、IL-1βCD80和CD86的mRNA表达。有趣的是，Andro诱导了髓系分化因子88(MyD88)的降解，并在脂多糖刺激下阻断了肿瘤坏死因子受体相关因子6(TRAF6)对MyD88的募集。用NH4Cl或MAP1LC3B(-/-)BMDCs阻断自噬蛋白降解可取消Andro诱导的MyD88降解。总之，Andro通过诱导MyD88的自噬蛋白分解来控制依赖于MyD88的细胞因子的激活，从而缓解银屑病，这可能是一种治疗银屑病的新策略。(C)2016 Elsevier Inc.保留所有权利。
Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1 beta in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAPILC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1 beta but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1 beta CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis. (C) 2016 Elsevier Inc. All rights reserved.