HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration A HINT FOR CNS REGENERATION
HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration A HINT FOR CNS REGENERATION
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HMGB1 蛋白不介导脊髓自发再生中的炎症反应，这是中枢神经系统再生的一个提示
DOI：
10.1074/jbc.m113.463810
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发表时间：
2013-06-21
影响因子：
4.8
通讯作者：
Wang, Yongjun
中科院分区：
文献类型：
--
作者：
Dong, Yingying;Gu, Yun;Wang, Yongjun
不受控制的过度炎症导致创伤性脊髓的继发性组织损伤，并且HMGB 1被强调为通过从坏死细胞或免疫细胞释放而引发恶性自我传播的炎症循环。一些有再生能力的脊椎动物已经进化出了一种未知的HMGB 1调控机制，以规避脊髓自发再生过程中的二次损伤。通过基因组调查，我们已经发现，两个旁系同源的HMGB 1广泛保留从鱼类的胚胎发育。然而，它们的时空表达和作用，如在最低的壁虎中所示，受到严格控制，以便在自发再生中产生有限的炎症。壁虎HMGB 1（gHMGB 1）的两个旁系同源物产生了不同的损伤和感染反应，gHMGB 1b在损伤的脊髓中显著上调。细胞内gHMGB 1b比gHMGB 1a诱导的巨噬细胞炎性细胞因子释放更少，并且这种作用可以通过交换炎症结构域中的一个氨基酸来转移。这两种细胞内蛋白能够介导神经元程序性凋亡，这已被证明产生可忽略的炎症反应。体内研究表明，细胞外蛋白不能在损伤的脊髓中触发炎性细胞因子的级联反应。信号转导分析发现gHMGB 1蛋白不能与细胞表面受体TLR 2和TLR 4结合激活炎症信号通路。然而，它们能够与晚期糖基化终产物的受体相互作用，通过激活NF κ B和Rac 1/Cdc 42信号传导来增强少突胶质细胞迁移。我们的研究结果表明，HMGB 1不介导自发性脊髓再生的炎症反应，但它促进中枢神经系统的再生。
Uncontrolled, excessive inflammation contributes to the secondary tissue damage of traumatic spinal cord, and HMGB1 is highlighted for initiation of a vicious self-propagating inflammatory circle by release from necrotic cells or immune cells. Several regenerative-competent vertebrates have evolved to circumvent the second damages during the spontaneous spinal cord regeneration with an unknown HMGB1 regulatory mechanism. By genomic surveys, we have revealed that two paralogs of HMGB1 are broadly retained from fish in the phylogeny. However, their spatial-temporal expression and effects, as shown in lowest amniote gecko, were tightly controlled in order that limited inflammation was produced in spontaneous regeneration. Two paralogs from gecko HMGB1 (gHMGB1) yielded distinct injury and infectious responses, with gHMGB1b significantly up-regulated in the injured cord. The intracellular gHMGB1b induced less release of inflammatory cytokines than gHMGB1a in macrophages, and the effects could be shifted by exchanging one amino acid in the inflammatory domain. Both intracellular proteins were able to mediate neuronal programmed apoptosis, which has been indicated to produce negligible inflammatory responses. In vivo studies demonstrated that the extracellular proteins could not trigger a cascade of the inflammatory cytokines in the injured spinal cord. Signal transduction analysis found that gHMGB1 proteins could not bind with cell surface receptors TLR2 and TLR4 to activate inflammatory signaling pathway. However, they were able to interact with the receptor for advanced glycation end products to potentiate oligodendrocyte migration by activation of both NF kappa B and Rac1/Cdc42 signaling. Our results reveal that HMGB1 does not mediate the inflammatory response in spontaneous spinal cord regeneration, but it promotes CNS regeneration.