TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury
TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury
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DOI：
10.1007/s00395-014-0415-z
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发表时间：
2014-09-01
影响因子：
9.5
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Liu, Yi;Lian, Kun;Tao, Ling
NLRP 3炎性体是引发急性无菌性炎症所必需的。最近的研究表明，NLRP 3炎性体上调并介导心肌缺血/再灌注（MI/R）损伤。然而，导致MI/R损伤激活NLRP 3炎性体的信号通路尚未完全阐明。C57 BL/6 J小鼠进行30 min缺血和3或24 h再灌注。缺血心脏表现出增强的炎性小体活化，如通过增加的NLRP 3表达和半胱天冬酶-1活性以及增加的IL-1 β和IL-18产生所证明的。心肌内NLRP 3 siRNA注射或腹腔内注射BAY 11-7028（一种炎性体抑制剂）减弱了巨噬细胞和中性粒细胞浸润，并降低了MI/R损伤，如通过心肌细胞凋亡和梗死面积所测量的。缺血心脏还表现出Txnip和NLRP 3之间增强的相互作用，这已被证明是激活NLRP 3的机制。心肌内Txnip siRNA注射也降低了梗死面积和NLRP 3活化。体外实验表明，NLRP 3在心肌微血管内皮细胞（CMECs）中表达，而在心肌细胞中几乎不表达。模拟缺血/再灌注（SI/R）刺激NLRP 3炎性小体激活CMECs，但不是在心肌细胞。此外，受到SI/R损伤的CMEC增加了Txnip和NLRP 3之间的相互作用。Txnip siRNA减少了NLRP 3炎性体活化和SI/R诱导的损伤，如通过CMEC中的LDH释放和半胱天冬酶-3活性所测量的。ROS清除剂可使TXNIP与NLRP 3解离，抑制CMECs中NLRP 3炎性体的活化。我们首次证明了TXNIP介导的CMECs中NLRP 3炎性体激活是MI/R损伤的一种新机制。阻断Txnip/NLRP 3信号传导以抑制NLRP 3炎性体的活化的干预可能是减轻MI/R损伤的新疗法。
NLRP3 inflammasome is necessary for initiating acute sterile inflammation. Recent studies have demonstrated that NLRP3 inflammasome is up-regulated and mediates myocardial ischemia/reperfusion (MI/R) injury. However, the signaling pathways that lead to the activation of NLRP3 inflammasome by MI/R injury have not been fully elucidated. C57BL/6J mice were subjected to 30 min ischemia and 3 or 24 h reperfusion. The ischemic heart exhibited enhanced inflammasome activation as evidenced by increased NLRP3 expression and caspase-1 activity and increased IL-1 beta and IL-18 production. Intramyocardial NLRP3 siRNA injection or an intraperitoneal injection of BAY 11-7028, an inflammasome inhibitor, attenuated macrophage and neutrophil infiltration and decreased MI/R injury, as measured by cardiomyocyte apoptosis and infarct size. The ischemic heart also exhibited enhanced interaction between Txnip and NLRP3, which has been shown to be a mechanism for activating NLRP3. Intramyocardial Txnip siRNA injection also decreased infarct size and NLRP3 activation. In vitro experiments revealed that NLRP3 was expressed in cardiac microvascular endothelial cells (CMECs), but was hardly expressed in cardiomyocytes. Simulated ischemia/reperfusion (SI/R) stimulated NLRP3 inflammasome activation in CMECs, but not in cardiomyocytes. Moreover, CMECs subjected to SI/R injury increased interactions between Txnip and NLRP3. Txnip siRNA diminished NLRP3 inflammasome activation and SI/R-induced injury, as measured by LDH release and caspase-3 activity in CMECs. ROS scavenger dissociated TXNIP from NLRP3 and inhibited the activation of NLRP3 inflammasome in the CMECs. For the first time, we demonstrated that TXNIP-mediated NLRP3 inflammasome activation in CMECs was a novel mechanism of MI/R injury. Interventions that block Txnip/NLRP3 signaling to inhibit the activation of NLRP3 inflammasomes may be novel therapies for mitigating MI/R injury.