Porphyromonas gingivalis attenuates ATP-mediated inflammasome activation and HMGB1 release through expression of a nucleoside-diphosphate kinase.
Porphyromonas gingivalis attenuates ATP-mediated inflammasome activation and HMGB1 release through expression of a nucleoside-diphosphate kinase.
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DOI：
10.1016/j.micinf.2015.03.010
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发表时间：
2015-05
影响因子：
5.8
通讯作者：
Ojcius DM
中科院分区：
文献类型：
--
作者：
Johnson L;Atanasova KR;Bui PQ;Lee J;Hung SC;Yilmaz Ö;Ojcius DM
许多细胞内病原体逃避先天性免疫应答，以便在感染的细胞内存活和增殖。我们表明，牙龈卟啉单胞菌，一种细胞内的机会致病菌，使用核苷二磷酸激酶（NDK）同源物，以抑制先天性免疫反应，由于刺激细胞外ATP，这作为一个危险信号，结合到P2 X7受体，并诱导炎症体和caspase-1的激活。因此，用野生型牙龈卟啉单胞菌感染牙龈上皮细胞（GEC）导致ATP诱导的半胱天冬酶-1活化的抑制。然而，ndk缺陷型牙龈卟啉单胞菌在减少ATP介导的半胱天冬酶-1活化和从感染的GEC分泌促炎细胞因子IL-1β方面不如野生型牙龈卟啉单胞菌有效。此外，牙龈卟啉单胞菌NDK调节高迁移率族蛋白B1（HMGB 1）的释放，这是一种促炎危险信号，它仍然与健康细胞中的染色质相关。出乎意料的是，感染野生型或ndk缺陷型牙龈卟啉单胞菌导致HMGB 1从细胞核释放到胞质溶胶。但当用ATP进一步刺激未感染的GEC时，HMGB 1被释放到细胞外空间，并且当用ndk缺陷型突变体感染ATP处理的细胞时，细胞释放的HMGB 1比野生型牙龈卟啉单胞菌更多。我们的研究结果表明，NDK在抑制P2 X7依赖性炎性小体激活和HMGB 1从感染的GECs释放中起着重要作用。
Many intracellular pathogens evade the innate immune response in order to survive and proliferate within infected cells. We show that Porphyromonas gingivalis, an intracellular opportunistic pathogen, uses a nucleoside-diphosphate kinase (NDK) homolog to inhibit innate immune responses due to stimulation by extracellular ATP, which acts as a danger signal that binds to P2X7 receptors and induces activation of an inflammasome and caspase-1. Thus, infection of gingival epithelial cells (GECs) with wild-type P. gingivalis results in inhibition of ATP-induced caspase-1 activation. However, ndk-deficient P. gingivalis is less effective than wild-type P. gingivalis in reducing ATP-mediated caspase-1 activation and secretion of the proinflammatory cytokine, IL-1β, from infected GECs. Furthermore, P. gingivalis NDK modulates release of high-mobility group protein B1 (HMGB1), a pro-inflammatory danger signal, which remains associated with chromatin in healthy cells. Unexpectedly, infection with either wild-type or ndk-deficient P. gingivalis causes release of HMGB1 from the nucleus to the cytosol. But HMGB1 is released to the extracellular space when uninfected GECs are further stimulated with ATP, and there is more HMGB1 released from the cells when ATP-treated cells are infected with ndk-deficient mutant than wild-type P. gingivalis. Our results reveal that NDK plays a significant role in inhibiting P2X7-dependent inflammasome activation and HMGB1 release from infected GECs.