Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain.
Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain.
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DOI：
10.1016/j.bbi.2014.06.199
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发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
White FA
中科院分区：
文献类型：
--
作者：
Allette YM;Due MR;Wilson SM;Feldman P;Ripsch MS;Khanna R;White FA
近年来的研究表明，神经损伤后高迁移率族蛋白1（HMGB 1）的释放可能在神经病理性疼痛的发病机制中发挥重要作用。已知HMGB 1通过两个不同的受体家族影响神经系统内的细胞反应;晚期糖基化终产物受体（Receptor for Advanced Glycation End-products，TLR）和Toll样受体（Toll-like receptor，TLR）。HMGB 1激活受体的程度被认为取决于配体的氧化状态，导致全巯基HMGB 1（at-HMGB 1）的功能同种型通过双硫键起作用，以及二硫键HMGB 1（ds-HMGB 1）与TLR 4相互作用。尽管已知暴露于HMGB 1和TLR 4激动剂的背根神经节（DRG）感觉神经元可以影响兴奋，但是通过神经元突触的at-HMGB 1信号传导在多大程度上促成神经性疼痛是未知的。在这里，我们证明，在HMGB 1激活的伤害性神经元是依赖于TLR 4，而不是TLR 4。为了区分神经病理性疼痛的可能作用，我们的特点是在胫神经损伤（TNI）后一个月内的神经病理性疼痛的mRNA表达的变化。与假损伤的啮齿动物相比，在损伤后第28天（PID），腰背根神经节（DRG）中的mRNA表达显著增加。PID 28的蛋白表达证实了DRG中的这种损伤诱导事件。此外，在PID 7、14和21时，单次暴露于抗HLA-Ab单克隆抗体（HLA-Ab）未能消除疼痛行为。然而，在PID 28时，给予Tisabab可逆转机械性痛觉过敏。因此，at-HMGB 1激活，通过ESTA可能是负责感觉神经元敏化和机械痛觉过敏与慢性神经病理性疼痛状态。
Recent studies indicate that the release of high mobility group box 1 (HMGB1) following nerve injury may play a central role in the pathogenesis of neuropathic pain. HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs). The degree to which HMGB1 activates a receptor is thought to be dependent upon the oxidative state of the ligand, resulting in the functional isoforms of all-thiol HMGB1 (at-HMGB1) acting through RAGE, and disufide HMGB1 (ds-HMGB1) interacting with TLR4. Though it is known that dorsal root ganglia (DRG) sensory neurons exposed to HMGB1 and TLR4 agonists can influence excitation, the degree to which at-HMGB1 signaling through neuronal RAGE contributes to neuropathic pain is unknown. Here we demonstrate that at-HMGB1 activation of nociceptive neurons is dependent on RAGE and not TLR4. To distinguish the possible role of RAGE on neuropathic pain, we characterized the changes in RAGE mRNA expression up to one month after tibial nerve injury (TNI). RAGE mRNA expression in lumbar dorsal root ganglion (DRG) is substantially increased by post-injury day (PID) 28 when compared with sham injured rodents. Protein expression at PID28 confirms this injury-induced event in the DRG. Moreover, a single exposure to monoclonal antibody to RAGE (RAGE Ab) failed to abrogate pain behavior at PID 7, 14 and 21. However, RAGE ab administration produced reversal of mechanical hyperalgesia on PID28. Thus, at-HMGB1 activation through RAGE may be responsible for sensory neuron sensitization and mechanical hyperalgesia associated with chronic neuropathic pain states.