Effect of enterohaemorrhagic Escherichia coli O157:H7-specific enterohaemolysin on interleukin-1β production differs between human and mouse macrophages due to the different sensitivity of NLRP3 activation
Effect of enterohaemorrhagic Escherichia coli O157:H7-specific enterohaemolysin on interleukin-1β production differs between human and mouse macrophages due to the different sensitivity of NLRP3 activation
复制标题
肠出血性大肠杆菌 O157:H7 特异性肠溶血素对白细胞介素 1β 产生的影响由于 NLRP3 激活的敏感性不同而在人和小鼠巨噬细胞之间存在差异。
DOI：
10.1111/imm.12442
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发表时间：
2015-06-01
期刊：
影响因子：
6.4
通讯作者：
Ren, Zhi-Hong
中科院分区：
文献类型：
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作者：
Cheng, Yu-Li;Song, Li-qiong;Ren, Zhi-Hong
人感染肠出血性大肠杆菌(EHEC)O157：H7可引起急性出血性结肠炎和严重溶血性尿毒症综合征。肠溶血素(EHX)在O157：H7介导的人类疾病发病机制中的作用尚不清楚。最近的研究揭示了炎症反应在人类O157：H7致病机制中的重要性。我们以前曾报道过Ehx能显著诱导人巨噬细胞产生IL-1。在这里，我们研究了EHX诱导的人和小鼠巨噬细胞产生IL-1的差异，并探索了NOD样受体家族，含有3个吡咯环的炎性小体(NLRP3)激活的潜在机制。与人分化的THP-1细胞和外周血单核细胞相比，EHX对小鼠巨噬细胞和脾细胞产生IL-1没有影响，这是因为在caspase-1激活时，前-IL-1被裂解成成熟的IL-1。此外，Ehx显著促进了O157：H7诱导的THP-1细胞的ATP释放，而这在小鼠巨噬细胞中没有检测到。共聚焦显微镜显示，在O157：H7攻击下，Ehx是THP-1细胞释放组织蛋白酶B的关键诱导剂，而不是小鼠IC-21细胞。抑制剂实验表明，O157：H7诱导的IL-1的产生在很大程度上依赖于caspase-1的激活，部分依赖于参与NLRP3激活的ATP信号和组织蛋白酶B的释放。此外，抑制K+外流可显著降低O157：H7诱导的IL-1的产生和细胞毒作用。这项研究的发现可能有助于阐明EHX是否以及如何在人类O157：H7感染中导致溶血性尿毒症综合征的发生。
Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infection in humans can cause acute haemorrhagic colitis and severe haemolytic uraemic syndrome. The role of enterohaemolysin (Ehx) in the pathogenesis of O157:H7-mediated disease in humans remains undefined. Recent studies have revealed the importance of the inflammatory response in O157:H7 pathogenesis in humans. We previously reported that Ehx markedly induced interleukin-1 (IL-1) production in human macrophages. Here, we investigated the disparity in Ehx-induced IL-1 production between human and mouse macrophages and explored the underlying mechanism regarding the activation of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes. In contrast to the effects on human differentiated THP-1 cells and peripheral blood mononuclear cells, Ehx exerted no effect on IL-1 production in mouse macrophages and splenocytes because of a disparity in pro-IL-1 cleavage into mature IL-1 upon caspase-1 activation. Additionally, Ehx significantly contributed to O157:H7-induced ATP release from THP-1 cells, which was not detected in mouse macrophages. Confocal microscopy demonstrated that Ehx was a key inducer of cathepsin B release in THP-1 cells but not in mouse IC-21 cells upon O157:H7 challenge. Inhibitor experiments indicated that O157:H7-induced IL-1 production was largely dependent upon caspase-1 activation and partially dependent upon ATP signalling and cathepsin B release, which were both involved in NLRP3 activation. Moreover, inhibition of K+ efflux drastically diminished O157:H7-induced IL-1 production and cytotoxicity. The findings in this study may shed light on whether and how the Ehx contributes to the development of haemolytic uraemic syndrome in human O157:H7 infection.