Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis
Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis
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DOI：
10.1038/ncomms7201
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发表时间：
2015-02-01
影响因子：
16.6
通讯作者：
Pinton, Paolo
中科院分区：
文献类型：
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作者：
Rimessi, Alessandro;Bezzerri, Valentino;Pinton, Paolo
囊性纤维化（CF）的常见病理学表现与以白细胞介素-1 β积累为特征的过度肺部炎症反应相关。CF气道上皮细胞显示出对铜绿假单胞菌的加剧的促炎反应;然而，尚不清楚这种增强的炎症反应是否是缺乏CF跨膜传导调节因子（CFTR）的细胞所固有的。在这里，我们证明了CF中炎症反应的程度和质量得到了铜绿假单胞菌依赖的线粒体扰动的支持，其中鞭毛蛋白是诱导剂，线粒体Ca 2+单向转运体（MCU）是NLRP 3激活和IL-1 β和IL-18加工的信号整合细胞器成员。我们的工作阐明了线粒体Ca 2+在铜绿假单胞菌依赖性炎症反应中对NLRP 3炎性小体的调节，并加深了我们对线粒体在Ca 2+依赖性炎症控制中的意义的理解。
The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1 beta accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa-dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca2+ uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1 beta and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca2+ in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca2+-dependent control of inflammation.