HMGB1-Driven Inflammation and Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated by TLR4.
HMGB1-Driven Inflammation and Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated by TLR4.
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动脉损伤后 HMGB1 驱动的炎症和内膜增生涉及 TLR4 介导的细胞特异性作用
DOI：
10.1161/atvbaha.115.305789
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Chen AF
中科院分区：
文献类型：
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作者：
Cai J;Yuan H;Wang Q;Yang H;Al-Abed Y;Hua Z;Wang J;Chen D;Wu J;Lu B;Pribis JP;Jiang W;Yang K;Hackam DJ;Tracey KJ;Billiar TR;Chen AF
腔内血管介入术（如血管成形术）会引发局部组织损伤导致的无菌炎症反应。这种反应驱动内膜增生（IH）的发展，进而可导致动脉闭塞。我们假设，普遍存在的核蛋白和损伤相关的分子模式分子，高迁移率族蛋白1（HMGB 1），是一种内源性介质，激活过程中导致IH后腔内损伤动脉壁。本研究的目的是调查是否减少HMGB 1水平或抑制其活性的方法抑制动脉损伤后的IH。在这里，我们表明，HMGB 1调节IH在小鼠颈动脉钢丝损伤模型。诱导的HMGB 1基因缺失或中和可防止颈动脉腔内损伤后IH、单核细胞募集和平滑肌细胞生长因子的产生。HMGB 1髓样分化因子2-toll样受体4（TLR 4）相互作用的特异性抑制剂P5779也显著抑制IH。HMGB 1缺失在该模型中通过TLR 4的整体缺失来模拟，并且通过TLR 4的骨髓特异性缺失而不是TLR 2或晚期糖基化终产物受体缺失来部分复制。已知可激活TLR 4信号传导的特定HMGB 1亚型（二硫键HMGB 1）刺激平滑肌细胞迁移并通过TLR 4产生单核细胞趋化蛋白1/CCL 2）。巨噬细胞还以TLR 4/髓样分化初级应答基因（88）/Trif依赖性方式应答二硫化物HMGB 1产生平滑肌细胞有丝分裂原。这些发现将HMGB 1及其受体TLR 4作为驱动导致腔内动脉损伤后IH的炎症事件的关键调节因子，并将该途径确定为限制IH以减弱损伤相关分子模式分子介导的血管炎症反应的可能治疗靶点。
Endoluminal vascular interventions such as angioplasty initiate a sterile inflammatory response resulting from local tissue damage. This response drives the development of intimal hyperplasia (IH) that, in turn, can lead to arterial occlusion. We hypothesized that the ubiquitous nuclear protein and damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1), is one of the endogenous mediators that activates processes leading to IH after endoluminal injury to the arterial wall. The aim of this study is to investigate whether approaches that reduce the levels of HMGB1 or inhibit its activity suppresses IH after arterial injury. Here, we show that HMGB1 regulates IH in a mouse carotid wire injury model. Induced genetic deletion or neutralization of HMGB1 prevents IH, monocyte recruitment, and smooth muscle cell growth factor production after endoluminal carotid artery injury. A specific inhibitor of HMGB1 myeloid differentiation factor 2–toll-like receptor 4 (TLR4) interaction, P5779, also significantly inhibits IH. HMGB1 deletion is mimicked in this model by global deletion of TLR4 and partially replicated by myeloid-specific deletion of TLR4 but not TLR2 or receptor for advanced glycation endproducts deletion. The specific HMGB1 isoform known to activate TLR4 signaling (disulfide HMGB1) stimulates smooth muscle cell to migrate and produce monocyte chemotactic protein 1/CCL2) via TLR4. Macrophages produce smooth muscle cell mitogens in response to disulfide HMGB1 also in a TLR4/myeloid differentiation primary response gene (88)/Trif-dependent manner. These findings place HMGB1 and its receptor, TLR4 as critical regulators of the events that drive the inflammation leading to IH after endoluminal arterial injury and identify this pathway as a possible therapeutic target to limit IH to attenuate damage-associated molecular pattern molecule–mediated vascular inflammatory responses.