Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.
Instigation of endothelial Nlrp3 inflammasome by adipokine visfatin promotes inter-endothelial junction disruption: role of HMGB1.
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DOI：
10.1111/jcmm.12657
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发表时间：
2015-12
影响因子：
5.3
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Chen Y;Pitzer AL;Li X;Li PL;Wang L;Zhang Y
最近的研究表明，炎症小体在血管疾病的发病机制中起着至关重要的作用。然而，这种炎症小体激活的病理相关性，特别是在血管细胞中，仍然很大程度上未知。在这里，我们研究了包含三个（Nlrp3）炎症小体的内皮（核苷酸结合寡聚化结构域）NOD样受体家族pyrin结构域在调节内皮间连接蛋白中的作用，内皮连接蛋白与内皮屏障功能障碍（肥胖相关内皮损伤的早期发作）有关。我们的研究结果表明，内脂素激活 Nlrp3 炎症小体显着降低培养的小鼠血管内皮 (VE) 细胞单层中内皮间连接蛋白的表达，包括紧密连接蛋白 ZO-1、ZO-2 和 occludin，以及粘附连接蛋白 VE-钙粘蛋白。这种内皮细胞中内脂素诱导的连接蛋白下调归因于内皮炎症小体依赖性 caspase-1 活性释放的高迁移率族盒蛋白 1 (HMGB1)。同样，在野生型小鼠的冠状动脉中，高脂饮食（HFD）治疗导致内皮连接蛋白 ZO-1、ZO-2、occludin 和 VE-cadherin 下调，同时伴随内皮细胞炎症小体激活和 HMGB1 表达增强以及 CD43+ T 细胞迁移至冠状动脉 动脉壁。相比之下，所有这些由 HFD 引起的冠状动脉改变在 Nlrp3 基因缺失的小鼠中都得到了预防。综上所述，这些数据强烈表明，内皮 Nlrp3 炎症小体的激活是由于内脂素等有害脂肪因子的作用增加而产生 HMGB1，HMGB1 以旁分泌或自分泌方式作用，破坏内皮间连接并增加内皮的细胞旁通透性，从而导致代谢紊乱期间内皮损伤的早期发生，例如 肥胖或高脂肪/胆固醇饮食。
Recent studies have indicated that the inflammasome plays a critical role in the pathogenesis of vascular diseases. However, the pathological relevance of this inflammasome activation, particularly in vascular cells, remains largely unknown. Here, we investigated the role of endothelial (Nucleotide‐binding Oligomerization Domain) NOD‐like receptor family pyrin domain containing three (Nlrp3) inflammasomes in modulating inter‐endothelial junction proteins, which are associated with endothelial barrier dysfunction, an early onset of obesity‐associated endothelial injury. Our findings demonstrate that the activation of Nlrp3 inflammasome by visfatin markedly decreased the expression of inter‐endothelial junction proteins including tight junction proteins ZO‐1, ZO‐2 and occludin, and adherens junction protein VE‐cadherin in cultured mouse vascular endothelial (VE) cell monolayers. Such visfatin‐induced down‐regulation of junction proteins in endothelial cells was attributed to high mobility group box protein 1 (HMGB1) release derived from endothelial inflammasome‐dependent caspase‐1 activity. Similarly, in the coronary arteries of wild‐type mice, high‐fat diet (HFD) treatment caused a down‐regulation of inter‐endothelial junction proteins ZO‐1, ZO‐2, occludin and VE‐cadherin, which was accompanied with enhanced inflammasome activation and HMGB1 expression in the endothelium as well as transmigration of CD43+ T cells into the coronary arterial wall. In contrast, all these HFD‐induced alterations in coronary arteries were prevented in mice with Nlrp3 gene deletion. Taken together, these data strongly suggest that the activation of endothelial Nlrp3 inflammasomes as a result of the increased actions of injurious adipokines such as visfatin produces HMGB1, which act in paracrine or autocrine fashion to disrupt inter‐endothelial junctions and increase paracellular permeability of the endothelium contributing to the early onset of endothelial injury during metabolic disorders such as obesity or high‐fat/cholesterol diet.