A toll-like receptor 9 antagonist reduces pain hypersensitivity and the inflammatory response in spinal cord injury
A toll-like receptor 9 antagonist reduces pain hypersensitivity and the inflammatory response in spinal cord injury
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DOI：
10.1016/j.nbd.2012.12.012
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发表时间：
2013-06-01
影响因子：
6.1
通讯作者：
Elkabes, Stella
中科院分区：
文献类型：
--
作者：
David, Brian T.;Ratnayake, Ayomi;Elkabes, Stella
Toll样受体（TLR）是对外源性病原体的先天性免疫应答的介质。它们还通过结合可能由受损细胞释放的内源性配体而参与与全身性损伤和非感染性疾病相关的无菌炎症。新出现的证据表明，一些TLR在神经系统损伤中起作用，特别是在损伤引起的疼痛和无菌性炎症中。然而，没有关于TLR家族成员TLR 9对创伤性脊髓损伤（SCI）的贡献的信息。此外，TLR 9配体在SCI功能结局（包括疼痛）中的治疗潜力尚未探索。我们报告，第一次，鞘内注射TLR 9拮抗剂，Cyridine-phosphate-guanosine oligodeoxynudeotide 2088（CpG ODN 2088），小鼠持续严重挫伤SCI，减少损伤诱导的热过敏。对疼痛敏感性降低潜在机制的研究表明，炎症反应减弱，表现为震中CD 11b-、CD 45-和CD 3-免疫反应细胞数量减少以及肿瘤坏死因子-α（TNF-α）表达减少。相反，鞘内递送TLR 9激动剂CpG ODN 1826增加了震中的炎性细胞数量和TNF-α表达。如脾组织学和血清细胞因子水平所示，CpG ODN 2088治疗似乎没有诱导全身性不良反应。我们认为CpG ODN 2088通过抑制炎症反应和TNF-α表达来抑制损伤诱导的热过敏。这项研究确定了以前未报道的CpG ODN 2088在SCI诱导的疼痛中的治疗作用。(C)2013 Elsevier Inc. All rights reserved.
Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile inflammation associated with systemic injury and non-infectious diseases via binding of endogenous ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in nervous system injury and especially in injury-elicited pain and sterile inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9 ligands in the functional outcomes of SCI, including pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist, cyridine-phosphate-guanosine oligodeoxynudeotide 2088 (CpG ODN 2088), to mice sustaining a severe contusion SCI, diminishes injury-induced heat hypersensitivity. Investigations on the potential mechanisms underlying the reduction in pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in tumor necrosis factor-alpha (TNF-alpha) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist, CpG ODN 1826, increased inflammatory cell numbers and TNF-alpha expression in the epicenter. The CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum cytokine levels. We propose that CpG ODN 2088 dampens injury-induced heat hypersensitivity by suppressing the inflammatory response and TNF-alpha expression. This investigation defines a previously unreported therapeutic role for CpG ODN 2088 in SCI-induced pain. (C) 2013 Elsevier Inc. All rights reserved.