The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock.
The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock.
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DOI：
10.1155/2017/6543237
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发表时间：
2017
影响因子：
4.6
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Chen X;Wang N;Zhu Y;Lu Y;Liu X;Zheng J
催化促炎细胞因子如IL-1β和IL-18成熟的NLRP 3炎性体的活化与许多种类的炎性病症有关并基本上涉及其中。氯喹（CQ）是一种传统的抗疟疾药物，也具有抗炎特性。在这项研究中，我们研究了CQ是否抑制NLRP 3炎性小体激活，从而赋予对小鼠内毒素休克的保护。CQ可减弱NF-κB和MAPK的活化，抑制LPS处理的小鼠骨髓源性巨噬细胞（BMDM）中IL-1β、IL-18和Nlrp 3的表达，表明其对NLRP 3活化的启动信号具有抑制作用。然后，CQ显示抑制BMDM中的半胱天冬酶-1活化和ASC斑点形成，这表明CQ还抑制炎性小体组装，这是NLRP 3炎性小体活化的第二个信号。在小鼠内毒素休克模型中，CQ有效地提高了存活率，并显著降低了血清、腹腔液和肺组织中IL-1β和IL-18的产生。此外，CQ降低了内毒素休克小鼠肺匀浆中NLRP 3和caspase-1 p10的蛋白水平，这可能解释了其体内抗炎活性和生命保护功效。总的来说，我们的研究结果证明了CQ的一个新作用，它促进了NLRP 3炎性小体的负调控，从而提供了对致死性内毒素休克的保护。
Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1β and IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ) is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF-κB and MAPK activation and prohibited expression of IL-1β, IL-18, and Nlrp3 in LPS treated murine bone marrow-derived macrophages (BMDMs), demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1β and IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock.