Bacterial Pore-Forming Toxins Promote the Activation of Caspases in Parallel to Necroptosis to Enhance Alarmin Release and Inflammation During Pneumonia.
Bacterial Pore-Forming Toxins Promote the Activation of Caspases in Parallel to Necroptosis to Enhance Alarmin Release and Inflammation During Pneumonia.
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DOI：
10.1038/s41598-018-24210-8
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发表时间：
2018-04-11
影响因子：
4.6
通讯作者：
Orihuela CJ
中科院分区：
文献类型：
--
作者：
Gonzalez-Juarbe N;Bradley KM;Riegler AN;Reyes LF;Brissac T;Park SS;Restrepo MI;Orihuela CJ
致孔性毒素是病原菌中最常见的毒力因子。它们导致膜通透性和细胞死亡。在这里，我们表明，呼吸上皮细胞(REC)在经历细菌致孔毒素(PFT)诱导的坏死性下垂的同时，经历了不依赖RIPK3的caspase激活。用泛半胱氨酸氨基转移酶抑制剂处理MLKL缺陷的REC，可以相加的方式保护REC免受PFT诱导的死亡。随后，通过免疫印迹和单抗染色，在发生坏死性下垂的REC中检测到caspase-2、-4和-10的切割版本。在经历革兰氏阴性和革兰氏阳性细菌性肺炎的小鼠和非人灵长类动物的肺样本中观察到caspase的激活。在细胞凋亡过程中，caspase的激活通常会导致细胞萎缩、核固缩和免疫静止性死亡。相反，在PFT诱导的坏死性下垂过程中，caspase活性增加了警报蛋白释放到细胞外环境。Caspase介导的alarmin的释放足以激活静息的巨噬细胞，导致IL-6的产生。在革兰氏阴性肺炎的小鼠模型中，caspase-2和-11的缺失，caspase-4的小鼠同源基因，减少了肺部炎症，免疫细胞渗透和肺损伤。因此，我们的研究描述了caspase激活与坏死性下垂并行的先前未知的作用，并表明它们的活性在细菌性肺炎中起着关键的促炎作用。
Pore-forming toxins are the most common virulence factor in pathogenic bacteria. They lead to membrane permeabilization and cell death. Herein, we show that respiratory epithelial cells (REC) undergoing bacterial pore-forming toxin (PFT)-induced necroptosis simultaneously experienced caspase activation independently of RIPK3. MLKL deficient REC treated with a pan-caspase inhibitor were protected in an additive manner against PFT-induced death. Subsequently, cleaved versions of caspases-2, -4 and -10 were detected within REC undergoing necroptosis by immunoblots and monoclonal antibody staining. Caspase activation was observed in lung samples from mice and non-human primates experiencing Gram-negative and Gram-positive bacterial pneumonia, respectively. During apoptosis, caspase activation normally leads to cell shrinkage, nuclear condensation, and immunoquiescent death. In contrast, caspase activity during PFT-induced necroptosis increased the release of alarmins to the extracellular milieu. Caspase-mediated alarmin release was found sufficient to activate resting macrophages, leading to Interleukin-6 production. In a mouse model of Gram-negative pneumonia, deletion of caspases -2 and -11, the mouse orthologue of caspase-4, reduced pulmonary inflammation, immune cell infiltration and lung damage. Thus, our study describes a previously unrecognized role for caspase activation in parallel to necroptosis, and indicates that their activity plays a critical pro-inflammatory role during bacterial pneumonia.
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影响因子：
3.1
作者：
delosToyos, JR;Mendez, FJ;Mitchell, TJ
通讯作者：
Mitchell, TJ
影响因子：
4.8
作者：
Guo, Y;Srinivasula, SM;Alnemri, ES
通讯作者：
Alnemri, ES
影响因子：
6.7
作者：
González-Juarbe N;Gilley RP;Hinojosa CA;Bradley KM;Kamei A;Gao G;Dube PH;Bergman MA;Orihuela CJ
通讯作者：
Orihuela CJ
DOI：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA
影响因子：
8
作者：
Krumschnabel, G.;Manzl, C.;Villunger, A.
通讯作者：
Villunger, A.