Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis.
Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis.
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组织蛋白酶B通过激活炎症小体促进细胞焦亡加重柯萨奇病毒B3诱发的心肌炎
DOI：
10.1371/journal.ppat.1006872
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发表时间：
2018-01
期刊：
影响因子：
6.7
通讯作者：
Xiang M
中科院分区：
文献类型：
--
作者：
Wang Y;Jia L;Shen J;Wang Y;Fu Z;Su SA;Cai Z;Wang JA;Xiang M
组织蛋白酶B（CatB）是一种半胱氨酸蛋白水解酶，广泛表达于多种细胞中，主要定位于溶酶体中。它有助于许多疾病的发病和发展。然而，CatB在病毒性心肌炎（VMC）中的作用从未被阐明。本研究通过腹腔注射柯萨奇病毒B_3（CVB_3）建立小鼠VMC模型。在第7天和第28天，我们发现CatB在VMC小鼠心脏中被显著激活。与接受等量CVB 3的野生型小鼠相比，CatB基因消融（Ctsb-/-）显著提高了存活率，减少了炎性细胞浸润，降低了血清心肌肌钙蛋白I水平，改善了心功能障碍，而不改变心脏中的病毒滴度。相反，Cstc-/-基因缺失显著增强心脏CatB水平，明显增加VMC的严重程度。此外，与对照组相比，我们发现VMC野生型小鼠心脏炎性小体被激活，Ctsb-/-小鼠心脏炎性小体被减弱，而Cstc-/-小鼠心脏炎性小体被进一步增强。结论：Ctsb-/-小鼠心肌炎性小体诱发的心肌细胞凋亡减少，Cstc-/-小鼠心肌炎性小体诱发的心肌细胞凋亡增加。提示CatB可能通过激活炎性小体和促进细胞凋亡来抑制CVB 3诱导的VMC。这一发现可能为VMC的治疗提供一种新的策略。严重的VMC可导致心源性猝死，尤其是在年轻人中，也是继发性扩张型心肌病的最常见原因。然而，目前我们仍然缺乏有效且具体的临床治疗方法。因此，迫切需要进一步探索其发病机制和新的治疗靶点。我们的研究结果表明，CatB，主要位于溶酶体中的半胱氨酸蛋白酶，在VMC小鼠腹腔注射CVB 3诱导的心脏被激活。CatB基因缺失可显著改善存活率、减轻心脏炎症、降低血清心肌肌钙蛋白I水平和缓解心功能障碍，而不会改变心脏中的病毒滴度。然而，消融其主要内源性抑制剂，胱抑素C，明显夸大了疾病的严重程度。从机制上讲，我们发现CatB可能通过激活NLRP 3炎性体和促进caspase-1诱导的细胞凋亡来影响VMC。这可能为VMC的治疗提供新的策略。
Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment. Severe VMC could lead to sudden cardiac death especially in youths, and is also the most common cause of secondary dilated cardiomyopathy. However, we still lack effective and specific clinical treatments currently. Therefore, further exploration of the pathogenesis and new therapeutic targets are urgently needed. Our results implied that CatB, a cysteine protease mainly located in the lysosome, is activated in the hearts of mice with VMC induced by intraperitoneal injection of CVB3. Genetic deletion of CatB significantly improves survival, attenuates cardiac inflammation, decreases serum cardiac troponin I levels and alleviates cardiac dysfunction, without altering virus titers in hearts. However, ablation of its main endogenous inhibitor, cystatin C, distinctly exaggerates the disease severity. Mechanistically, we found that CatB influences VMC probably by activating the NLRP3 inflammasome and promoting caspase-1-induced pyroptosis. This may provide a potential new therapeutic strategy for VMC.
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影响因子：
8.7
作者：
Man SM;Karki R;Kanneganti TD
通讯作者：
Kanneganti TD
DOI：
10.1016/j.bbamcr.2014.11.012
发表时间：
2015-02
影响因子：
5.1
作者：
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影响因子：
1.7
作者：
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通讯作者：
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DOI：
10.1002/prca.201300105
发表时间：
2014-06
期刊：
Proteomics. Clinical applications
影响因子：
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作者：
Aggarwal N;Sloane BF
通讯作者：
Sloane BF
影响因子：
30.5
作者：
通讯作者：
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