Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima-city, Tokushima 770-8503, Japan; Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Atherosclerosis. 2013 Dec;231(2):227-33. doi: 10.1016/j.atherosclerosis.2013.09.010. Epub 2013 Oct 2.
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.
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.
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.
死亡细胞释放的内源性配体，如高迁移率族蛋白 B1（HMGB1）和核酸，与 Toll 样受体（TLR）结合。由于 TLR9 通过检测细菌和内源性 DNA 参与微生物和无菌性炎症，我们研究了其在血管损伤小鼠模型中炎症和损伤形成中的作用。
C57BL/6（WT）和 TLR9 KO 小鼠接受金属丝介导的血管损伤。抗 HMGB1 抗体和纯化的 HMGB1 蛋白通过明胶水凝胶在损伤动脉周围进行慢性给药，并评估损伤后 4 周的新生内膜形成。此外，在骨髓嵌合小鼠（WT 骨髓转入 TLR KO 小鼠；TLR9 KO 骨髓转入 WT 小鼠）中进行相同的血管损伤。我们还评估了 HMGB1 和 CpG-ODN 对小鼠巨噬细胞产生炎症细胞因子的作用。在血管损伤后的野生型小鼠中，抗 HMGB1 抗体显著减少了新生内膜形成，HMGB1 蛋白加速了新生内膜增生。HMGB1 在 TLR9 KO 小鼠中未能加速病变形成。骨髓移植研究表明，骨髓来源细胞中的 TLR9 在新生内膜形成中发挥了基本作用。在体外，HMGB1 和 CpG-ODN 协同诱导巨噬细胞产生炎症细胞因子。
HMGB1 作为一种内源性炎症和损伤形成介质，通过 TLR9 途径对血管损伤作出反应。HMGB1 和/或 TLR9 的阻断可能代表治疗动脉粥样硬化的一种新方法。
