动脉损伤后HMGB1驱动的炎症和内膜增生涉及由TLR4介导的细胞特异性作用。
HMGB1-Driven Inflammation and Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated by TLR4.
作者信息
Cai Jingjing, Yuan Hong, Wang Qingde, Yang Huan, Al-Abed Yousef, Hua Zhong, Wang Jiemei, Chen Dandan, Wu Jinze, Lu Ben, Pribis John P, Jiang Weihong, Yang Kan, Hackam David J, Tracey Kevin J, Billiar Timothy R, Chen Alex F
机构信息
From the Center of Clinical Pharmacology of the Third Xiangya Hospital (J.C., H.Y., Q.W., Z.H., J. Wu), the Center of Vascular Disease and Translational Medicine (A.F.C.), Department of Cardiology of the Third Xiangya Hospital (J.C., H.Y., W.J., K.Y.), and Department of Hematology of the Third Xiangya Hospital (B.L.), Central South University, Changsha, China; Department of Surgery, University of Pittsburgh School of Medicine, PA (J.C., Q.W., Z.H., J. Wang, D.C., J. Wu, J.P.P., D.J.H., T.R.B., A.F.C.); and Laboratory of Biomedical Science, the Feinstein Institute for Medical Research, Manhasset, New York (H.Y., Y.A.-A., K.J.T.).
出版信息
Arterioscler Thromb Vasc Biol. 2015 Dec;35(12):2579-93. doi: 10.1161/ATVBAHA.115.305789. Epub 2015 Oct 29.
OBJECTIVE
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.
APPROACH AND RESULTS
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.
CONCLUSIONS
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.
目的
血管腔内介入治疗如血管成形术会引发因局部组织损伤导致的无菌性炎症反应。这种反应会促使内膜增生（IH）的发展，进而可能导致动脉闭塞。我们推测，普遍存在的核蛋白及损伤相关分子模式分子高迁移率族蛋白B1（HMGB1）是动脉壁腔内损伤后激活导致内膜增生过程的内源性介质之一。本研究的目的是探究降低HMGB1水平或抑制其活性的方法是否能抑制动脉损伤后的内膜增生。
方法与结果
在此，我们表明HMGB1在小鼠颈动脉钢丝损伤模型中调节内膜增生。诱导性基因缺失或HMGB1中和可预防腔内颈动脉损伤后的内膜增生、单核细胞募集和平滑肌细胞生长因子产生。HMGB1髓样分化因子2- Toll样受体4（TLR4）相互作用的特异性抑制剂P5779也能显著抑制内膜增生。在该模型中，通过全局缺失TLR4可模拟HMGB1缺失，通过髓样特异性缺失TLR4可部分复制该现象，但缺失TLR2或晚期糖基化终产物受体则不能。已知可激活TLR4信号传导的特定HMGB1异构体（二硫键HMGB1）通过TLR4刺激平滑肌细胞迁移并产生单核细胞趋化蛋白1/CCL2）。巨噬细胞也以TLR4/髓样分化初级反应基因（88）/Trif依赖性方式响应二硫键HMGB1产生平滑肌细胞有丝分裂原。
结论
这些发现表明HMGB1及其受体TLR4是腔内动脉损伤后驱动导致内膜增生炎症事件的关键调节因子，并确定该途径作为限制内膜增生以减轻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。
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