The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases
The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases
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DOI：
10.2119/molmed.2013.00164
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发表时间：
2014-01-01
影响因子：
5.7
通讯作者：
Pisetsky, David S.
中科院分区：
文献类型：
--
作者：
Magna, Melinda;Pisetsky, David S.
高迁移率组框1 （HMGB1）蛋白是一种丰富的蛋白，一旦位于细胞外位置，可促进炎症和自身免疫性疾病的发病。这种易位可以在免疫细胞激活和细胞死亡时发生，释放条件与不同同种异构体的表达有关。这些同工异构体是翻译后修饰的结果，23、45和106位的三种半胱氨酸的氧化还原状态对活性至关重要。根据这些残基的氧化还原状态，HMGB1可以通过toll样受体4 （TLR4）诱导细胞因子的产生，或通过CXCR4结合趋化因子CXCL12刺激促进趋化。完全氧化的HMGB1是无活性的。因此，在炎症性疾病过程中，HMGB1可以根据其氧化还原状态发挥动态作用。作为一种产生警报的机制，细胞死亡是HMGB1的重要来源，尽管每一种主要的细胞死亡形式（坏死、凋亡、热亡和NETosis）都可以导致HMGB1的不同亚型以及HMGB1与核小体的不同程度的关联。HMGB1与核小体的关联可能通过产生核物质来促进系统性红斑狼疮的发病机制，核物质的免疫特性因警报蛋白的存在而增强。由于血液或组织中的HMGB1水平在许多炎症和自身免疫性疾病中升高，该分子可以作为独特的生物标志物，也可以作为阻断其各种活性的新疗法的靶标。
High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from post-translational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.