A crucial role of HMGB1 in orofacial and widespread pain sensitization following partial infraorbital nerve transection
A crucial role of HMGB1 in orofacial and widespread pain sensitization following partial infraorbital nerve transection
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HMGB1 在部分眶下神经横断后口面部和广泛疼痛敏化中的关键作用
DOI：
10.1016/j.bbi.2020.05.020
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发表时间：
2020-08-01
影响因子：
15.1
通讯作者：
Zhang, Shi-Hong
中科院分区：
文献类型：
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作者：
Hu, Ting-Ting;Yu, Jie;Zhang, Shi-Hong
临床研究表明，口面部疼痛，如三叉神经病理性疼痛，经常扩散到邻近或对侧对称区域(镜像性疼痛)，甚至蔓延到身体远处(广泛性疼痛)(Türp等人，1998，Sipiläet al.，2005)。广泛性疼痛比口面部疼痛更持久，并与更多的感觉和情感痛苦有关(Krause等人，1989，Toomey等人，1984)。最近，我们报道了小鼠部分眶下神经切断(p-ion X)导致超敏反应从口面部向身体远端部位的远程扩散，伴随着中枢敏感化的吻尾传递和小胶质细胞沿脊髓的激活(Zhang等，2016)。随后，我们发现脊髓TLR4信号参与了触觉异常痛觉的传播，但不参与热痛觉过敏的传播(Hu等人，2018年)。这些研究表明，脊髓中的小胶质细胞和TLR4相关的神经炎症有助于疼痛敏感化的传播，从而为广泛超敏的病理生理机制提供了一些线索。高迁移率族蛋白1(HMGB1)是一种高度保守的非组蛋白核蛋白，属于损伤相关分子模式(DAMP)家族。HMGB1通常位于细胞核，参与调节染色质结构和基因转录(Tung等人，2014)。在某些条件下，HMGB1要么从坏死的细胞中被动释放，要么从活的但“应激”的细胞中被转移到细胞质中主动分泌。在中枢神经系统(CNS)中，HMGB1的细胞来源涉及胶质细胞和神经元，这些细胞的释放模式在时间上是不同的，这意味着其作用的复杂性(Sun等人，2015)。作为一种警报，细胞外HMGB1被认为通过与多种受体相互作用激活先天性和获得性免疫并驱动宿主炎症反应，这些受体包括晚期糖基化终产物受体(RAGE)、Toll样受体(TLR)2和TLR4以及其他受体(Lotze和Tracey，2005，Bertheloot和Latz，2017)。人们已经认识到，中枢神经系统中的HMGB1在脑缺血或创伤性损伤、多发性硬化症和神经病理性疼痛等多种疾病中发挥着重要作用，并可能成为潜在的治疗靶点(Singh等人，2016，Agalave和Svensson，2015，Laird等人，2014)。
Clinical studies show that orofacial pain, such as trigeminal neuropathic pain, often spreads to adjacent or contralateral symmetrical area (mirror-image pain), even to distant body regions (widespread pain)(Türp et al., 1998, Sipilä et al., 2005). Widespread pain is more persistent than the pain in the orofacial area and is associated with more sensory and affective distress (Krause et al., 1989, Toomey et al., 1984). Recently, we reported that partial infraorbital nerve transection (p-IONX) in mice induces long-range spread of hypersensitivity from the orofacial region to distant body parts, which is accompanied with rostral-caudal transmission of central sensitization and microglia activation along the spinal cord (Zhang et al., 2016). Subsequently, we found that spinal TLR4 signaling participates in the spread of tactile allodynia but not thermal hyperalgesia (Hu et al., 2018). These studies suggest that microglia and TLR4-related neuroinflammation in the spinal cord contribute to the spread of pain sensitization, shedding some light on the pathophysiological mechanism of widespread hypersensitivity. However, pivotal factors involved in the spread of spinal neuroinflammation remain to be identified.High mobility group box 1 (HMGB1) is a highly conserved non-histone nuclear protein and belongs to the damage-associated-molecular-pattern (DAMP) family. HMGB1 is usually located in the nucleus and participates in regulating chromatin structure and gene transcription (Tsung et al., 2014). Under certain conditions, HMGB1 is either passively released from necrotic cells or actively secreted from alive but “stressed” cells after being translocated into the cytoplasm. In the central nervous system (CNS), the cellular source of HMGB1 involves glias and neurons and the release pattern from these cells is temporally differential, implying the complexity of its action (Sun et al., 2015). As an alarmin, the extracellular HMGB1 is believed to activate innate and adaptive immunity and drives host inflammatory responses via interacting with multiple receptors, including the receptor for advanced glycation endproducts (RAGE), toll-like receptor (TLR) 2 and TLR4, as well as other receptors (Lotze and Tracey, 2005, Bertheloot and Latz, 2017). It has been recognized that HMGB1 in the CNS plays important roles in a variety of diseases such as ischemic or traumatic brain injury, multiple sclerosis and neuropathic pain, and may serve as a potential therapeutic target (Singh et al., 2016, Agalave and Svensson, 2015, Laird et al., 2014).