Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts
Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts
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一氧化碳释放分子3通过抑制心肌成纤维细胞NLRP3炎性体激活改善脓毒症小鼠心肌功能
DOI：
10.1007/s00395-017-0603-8
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发表时间：
2017-03-01
影响因子：
9.5
通讯作者：
Rui, Tao
中科院分区：
文献类型：
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作者：
Zhang, Wenbo;Tao, Aibin;Rui, Tao
NLRP 3炎性小体是一种细胞内多蛋白复合物，控制白细胞介素（IL）-1 β和IL-18的成熟和释放。内源性一氧化碳（CO）具有抗炎作用。本研究的目的是评估一氧化碳释放分子-3（CORM-3）依赖性调节心脏成纤维细胞（CF）中NLRP 3炎性小体的作用/机制及其对脓毒症心肌功能的影响。在用脂多糖（LPS）引发NLRP 3炎性小体之前或在用三磷酸腺苷（ATP）活化之后，用CORM-3或失活CORM-3（iCORM-3）处理CF。平行地，用LPS/ATP刺激的CF的上清液或含有IL-1 β、IL-18和HMGB 1的细胞因子混合物（Cyto-mix）攻击心肌细胞（CM）。在体内，在LPS诱导脓毒症（内毒素血症）之前或之后用CORM-3处理小鼠。用CORM-3预处理CF防止LPS诱导的NLRP 3和pro-IL-1 β表达的增加。在ATP之前用CORM-3处理CF防止了ATP诱导的NLRP 3炎性体的活化。用LPS/ATP包裹CF促进NLRP 3与接头ASC（含有半胱天冬酶募集结构域的凋亡相关斑点样蛋白）的相互作用，这被CORM-3阻止。用含有LPS/ATP或Cyto-mix（IL-1 β、IL-18和HMGB 1）的CF上清液处理CM导致CM凋亡，其被CORM-3或IL-1受体拮抗剂减弱。最后，心肌NLRP 3炎性体激活和心肌功能障碍在脓毒症小鼠被CORM-3消除。在患有败血症的NLRP 3缺陷小鼠中，CORM-3在改善心肌功能方面没有显示出额外的益处。我们的研究结果表明，CORM-3通过阻断NLRP 3与衔接蛋白ASC的相互作用来抑制NLRP 3炎性体激活，并减轻脓毒症小鼠的心肌功能障碍。
The NLRP3 inflammasome is an intracellular multiple-protein complex that controls the maturation and release of interleukin (IL)-1 beta and IL-18. Endogenous carbon monoxide (CO) is anti-inflammatory. The aim of this study was to assess the effects/mechanisms of CO-releasing molecule-3 (CORM-3)-dependent modulation of the NLRP3 inflammasome in cardiac fibroblasts (CF) and its effect on myocardial function in sepsis. CF were treated with CORM-3 or inactive CORM-3 (iCORM-3) before NLRP3 inflammasome priming with lipopolysaccharides (LPS) or following activation with adenosine triphosphate (ATP). In parallel, cardiomyocytes (CM) were challenged with supernatants of LPS/ATP-stimulated CF or a cytokine mixture (Cyto-mix) containing IL-1 beta, IL-18, and HMGB1. In vivo, mice were treated with CORM-3 before or after LPS to induce sepsis (endotoxemia). Pretreatment of CF with CORM-3 prevented an LPS-induced increase in NLRP3 and pro-IL-1 beta expression. Treatment of CF with CORM-3 before ATP prevented ATP-induced activation of the NLRP3 inflammasome. Challenging CF with LPS/ATP promoted NLRP3 interactions with adaptor ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which was prevented by CORM-3. Challenging CM with supernatants of CF with LPS/ATP or Cyto-mix (IL-1 beta, IL-18, and HMGB1) resulted in CM apoptosis, which was attenuated with either a CORM-3 or IL-1 receptor antagonist. Finally, myocardial NLRP3 inflammasome activation and myocardial dysfunction in septic mice were abolished by CORM-3. In NLRP3-deficient mice with sepsis, CORM-3 did not show additional benefits in improving myocardial function. Our results indicate that CORM-3 suppresses NLRP3 inflammasome activation by blocking NLRP3 interactions with the adaptor protein ASC and attenuates myocardial dysfunction in mice with sepsis.