Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis.
Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis.
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DOI：
10.1016/j.pain.2011.09.020
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发表时间：
2011-12
期刊：
影响因子：
7.4
通讯作者：
Yaksh TL
中科院分区：
文献类型：
--
作者：
Christianson CA;Dumlao DS;Stokes JA;Dennis EA;Svensson CI;Corr M;Yaksh TL
关节炎的临床可感知体征消退后的持续疼痛构成了治疗挑战，免疫抑制疗法不能满足这种医学需求。为了研究这种向持续性疼痛的转化，我们利用了K/BxN血清转移关节炎模型，尽管可见炎症消退，但该模型具有持续的机械超敏反应。Toll样受体（TLR）4已被认为是神经病理性和其他疼痛模型中的潜在治疗靶点。我们比较了野生型（WT）和Tlr 4 −/−小鼠血清转移关节炎和机械超敏反应的相对过程。在WT和Tlr 4 −/−小鼠中，K/BxN血清转移在第4-22天诱导了相似的关节肿胀和炎症。与WT小鼠不同，Tlr 4 −/−小鼠在外周炎症消退后表现出机械超敏反应的显著逆转和神经胶质活化标志物的减少。在第6、9和12天鞘内（IT）递送TLR 4拮抗剂LPS-RS（10μg）可消除WT关节炎小鼠向持续性机械超敏反应的转变，而随后的给药无影响。我们利用脂质组学LC/MS/MS方法来确定与媒介物处理的对照相比，在早期LPS-RS处理后生物活性脂质种类的脊髓概况。与IT LPS-RS处理的小鼠相比，WT关节炎小鼠在第6天具有降低的抗炎性前列腺素15 d-PGJ 2的脊髓水平。在第6天直接IT应用15 d-PGJ 2（0.5μg）在15分钟内改善了关节炎小鼠的机械超敏性。因此，TLR 4信号转导改变了血清转移模型中的脊髓生物活性脂质谱，并在从急性到慢性炎症后机械超敏反应的转变中发挥了关键作用。
Persistent pain after resolution of clinically appreciable signs of arthritis poses a therapeutic challenge and immunosuppressive therapies do not meet this medical need. To investigate this conversion to persistent pain, we utilized the K/BxN serum transfer arthritis model, which has persistent mechanical hypersensitivity despite the resolution of visible inflammation. Toll-like receptor (TLR) 4 has been implicated as a potential therapeutic target in neuropathic and other pain models. We compared the relative courses of serum transfer arthritis and mechanical hypersensitivity in wild type (WT) and Tlr4−/− mice. K/BxN serum transfer induced similar joint swelling and inflammation from days 4–22 in WT and Tlr4−/− mice. Unlike WT mice, Tlr4−/− mice displayed a significant reversal in mechanical hypersensitivity and diminished appearance of glial activation markers after resolution of peripheral inflammation. Intrathecal (IT) delivery of a TLR4 antagonist, LPS-RS (10μg), on days 6, 9, and 12 abrogated the transition to persistent mechanical hypersensitivity in WT arthritic mice, while later administration had no impact. We utilized a lipodomics LC/MS/MS methodology to determine spinal cord profiles of bioactive lipid species following early LPS-RS treatment compared to vehicle treated controls. WT arthritic mice had reduced spinal levels of the anti-inflammatory prostaglandin 15d-PGJ2 on day 6, compared to IT LPS-RS treated mice. Direct IT application of 15d-PGJ2 (0.5μg) on day 6 improved mechanical hypersensitivity in arthritic mice within 15 minutes. Hence, TLR4 signaling altered spinal bioactive lipid profiles in the serum transfer model and played a critical role in the transition from acute to chronic post-inflammatory mechanical hypersensitivity.
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