HMGB1 plays a critical role in vascular inflammation and lesion formation via toll-like receptor 9
HMGB1 plays a critical role in vascular inflammation and lesion formation via toll-like receptor 9
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DOI：
10.1016/j.atherosclerosis.2013.09.010
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发表时间：
2013-12-01
期刊：
影响因子：
5.3
通讯作者：
Sata, Masataka
中科院分区：
文献类型：
--
作者：
Hirata, Yoichiro;Kurobe, Hirotsugu;Sata, Masataka
目的：内源性配体如高迁移率族蛋白1（HMGB 1）和核酸由死亡细胞释放并结合Toll样受体（TLR）。由于TLR 9是通过检测细菌和内源性DNA参与微生物和无菌炎症，我们研究了其在炎症和病变形成中的作用，在小鼠模型vascular injury.Methods和results：C57 BL/6（WT）和TLR 9 KO小鼠进行线介导的血管损伤。将抗HMGB 1抗体和纯化的HMGB 1蛋白通过明胶水凝胶长期递送到损伤的动脉周围，并在损伤后4周评价新生内膜形成。此外，在骨髓嵌合小鼠中进行相同的血管损伤（WT骨髓进入TLR KO小鼠; TLR 9 KO骨髓进入WT小鼠）。我们还评估了小鼠巨噬细胞对HMGB 1和CpG-ODN的炎症细胞因子的产生。在血管损伤后的野生型小鼠中，抗HMGB 1抗体显著减少新生内膜形成，HMGB 1蛋白加速新生内膜增生。HMGB 1未能加速TLR 9 KO小鼠的病变形成。骨髓移植研究表明，骨髓来源的细胞中的TLR 9在新生内膜形成中起基础作用。在体外，HMGB 1和CpG-ODN协同诱导的炎症细胞因子的生产由macrophage.Conclusions：HMGB 1作为一种内源性介质的炎症和病变形成通过TLR 9途径在血管损伤的反应。阻断HMGB 1和/或TLR 9可能是治疗动脉粥样硬化的一种新方法。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Objective: Endogenous ligands such as high-mobility group box 1 (HMGB1) and nucleic acids are released by dying cells and bind to Toll-like receptors (TLRs). As TLR9 is involved in both microbial and sterile inflammation by detecting both bacterial and endogenous DNA, we investigated its role in inflammation and lesion formation in a mouse model of vascular injury.Methods and results: C57BL/6 (WT) and TLR9 KO mice were subjected to wire-mediated vascular injury. Anti-HMGB1 antibody and purified HMGB1 protein were chronically delivered around the injured arteries by gelatin hydrogel, and neointima formation at 4 weeks after injury was evaluated. In addition, the same vascular injury was performed in bone-marrow chimeric mice (WT bone marrow into TLR KO mice; TLR9 KO bone marrow into WT mice). We also evaluated the production of inflammatory cytokines by mouse macrophages in response to HMGB1 and CpG-ODN. In wild-type mice after vascular injury, anti-HMGB1 antibody significantly reduced neointima formation and HMGB1 protein accelerated neointima hyperplasia. HMGB1 failed to accelerate lesion formation in TLR9 KO mice. The bone marrow transplantation study revealed that TLR9 in bone marrow-derived cells played a fundamental role in neointima formation. In vitro, HMGB1 and CpG-ODN synergistically induced the production of inflammatory cytokines by macrophages.Conclusions: HMGB1 serves as an endogenous mediator of inflammation and lesion formation via the TLR9 pathway in response to vascular injury. Blockade of HMGB1 and/or TLR9 may represent a novel approach to treating atherosclerosis. (C) 2013 Elsevier Ireland Ltd. All rights reserved.