Endothelial Nlrp3 inflammasome activation associated with lysosomal destabilization during coronary arteritis.
Endothelial Nlrp3 inflammasome activation associated with lysosomal destabilization during coronary arteritis.
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DOI：
10.1016/j.bbamcr.2014.11.012
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发表时间：
2015-02
影响因子：
5.1
通讯作者：
Li, Pin-Lan
中科院分区：
文献类型：
--
作者：
Chen, Yang;Li, Xiang;Boini, Krishna M.;Pitzer, Ashley L.;Gulbins, Erich;Zhang, Yang;Li, Pin-Lan
炎性小体在血管疾病的发展中起关键作用。然而，激活内皮细胞中炎性小体的分子机制以及这种炎性小体激活的相关性远不清楚。在此，我们研究了干酪乳杆菌（Lactobacillus casei，L.）酪蛋白）细胞壁碎片（LCWE）在川崎小鼠模型中的作用。在用LCWE治疗的小鼠中，在冠状动脉炎期间观察到与血管细胞粘附蛋白1（VCAM-1）表达增加和内皮-白细胞粘附相关的内皮功能障碍。与此同时，冠状动脉内皮细胞也出现炎症小体活化，表现为caspase-1活性和IL-1β产生明显增加。在培养的内皮细胞中，LCWE诱导Nlrp 3炎性小体形成、半胱天冬酶-1活化和IL-1β产生，其被Nlrp 3基因沉默或溶酶体膜稳定剂如秋水仙碱、地塞米松和神经酰胺阻断。然而，钾通道阻滞剂格列本脲或氧自由基清除剂N-乙酰-L-半胱氨酸对LCWE诱导的炎性小体激活没有影响。LCWE还增加了内皮细胞溶酶体膜的通透性，并触发溶酶体组织蛋白酶B释放到胞质溶胶中。沉默组织蛋白酶B阻断LCWE诱导的内皮细胞中Nlrp 3炎性小体的形成和活化。在体内，用组织蛋白酶B抑制剂治疗小鼠也消除了LCWE诱导的冠状动脉内皮炎性小体活化。结论：LCWE增强了溶酶体膜的透化和随后的溶酶体组织蛋白酶B的释放，导致内皮Nlrp 3炎性体的激活，这可能有助于冠状动脉炎的发展。
Inflammasomes play a critical role in the development of vascular diseases. However, the molecular mechanisms activating the inflammasome in endothelial cells and the relevance of this inflammasome activation is far from clear. Here, we investigated the mechanisms by which Nlrp3 inflammasome is activated to result in endothelial dysfunction during coronary arteritis by Lactobacillus casei (L. casei) cell wall fragments (LCWE) in a mouse model for Kawasaki disease. Endothelial dysfunction associated with increased vascular cell adhesion protein 1 (VCAM-1) expression and endothelial-leukocyte adhesion was observed during coronary arteritis in mice treated with LCWE. Accompanied with these changes, the inflammasome activation was also shown in coronary arterial endothelium, which was characterized by a marked increase in caspase-1 activity and IL-1β production. In cultured endothelial cells, LCWE induced Nlrp3 inflammasome formation, caspase-1 activation and IL-1β production, which were blocked by Nlrp3 gene silencing or lysosome membrane stabilizing agents such as colchicine, dexamethasome, and ceramide. However, a potassium channel blocker glibenclamide or an oxygen free radical scavenger N-Acetyl-L-cysteine had no effects on LCWE-induced inflammasome activation. LCWE also increased endothelial cell lysosomal membrane permeability and triggered lysosomal cathepsin B release into cytosol. Silencing cathepsin B blocked LCWE-induced Nlrp3 inflammasome formation and activation in endothelial cells. In vivo, treatment of mice with cathepsin B inhibitor also abolished LCWE-induced inflammasome activation in coronary arterial endothelium. It is concluded that LCWE enhanced lysosomal membrane permeabilization and consequent release of lysosomal cathepsin B, resulting in activation of endothelial Nlrp3 inflammasome, which may contribute to the development of coronary arteritis.
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DOI：
10.4049/jimmunol.0802367
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bryan NB;Dorfleutner A;Rojanasakul Y;Stehlik C
通讯作者：
Stehlik C
影响因子：
--
作者：
Gattorno, Marco;Martini, Alberto
通讯作者：
Martini, Alberto
影响因子：
4.4
作者：
Hoegen, Tobias;Tremel, Nadin;Koedel, Uwe
通讯作者：
Koedel, Uwe
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
3.7
作者：
Hinz, B;Hirschelmann, R
通讯作者：
Hirschelmann, R