Porphyromonas gingivalis Differentially Modulates Apoptosome Apoptotic Peptidase Activating Factor 1 in Epithelial Cells and Fibroblasts
Porphyromonas gingivalis Differentially Modulates Apoptosome Apoptotic Peptidase Activating Factor 1 in Epithelial Cells and Fibroblasts
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DOI：
10.1016/j.ajpath.2017.10.014
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发表时间：
2018-02-01
影响因子：
6
通讯作者：
Huck, Olivier
中科院分区：
文献类型：
--
作者：
Bugueno, Isaac M.;Batool, Fareeha;Huck, Olivier
牙龈卟啉单胞菌能够侵入并调节宿主的免疫反应以促进其存活。这种细菌调节细胞周期和程序性细胞死亡，导致牙周病变恶化。几种分子途径已被确定为细胞凋亡的关键触发因子，包括溶酶体凋亡肽酶激活因子1（APAF-1）。Apaf-1和X连锁凋亡抑制蛋白（X-linked inhibitor of apoptosis protein，Xip）mRNA在健康人和慢性牙周炎患者牙龈组织中的表达差异（Apaf-1，19.2倍; caspase-9，14.5倍; caspase-3，6.8倍; Xip：2.5倍）（P < 0.05），提示它们在牙周炎中的潜在作用。在由牙龈卟啉单胞菌浸泡的结扎线诱导的小鼠实验性牙周炎模型中也观察到APAF-1的蛋白表达增加。在体外，观察到牙龈卟啉单胞菌靶向APAF-1、XIAP、半胱天冬酶-3和半胱天冬酶-9，以在mRNA和蛋白质水平上抑制上皮细胞死亡。在成纤维细胞中观察到相反的效果，其中牙龈卟啉单胞菌增加细胞死亡和凋亡。为了评估观察到的效应是否与APAF-1相关，用靶向Apaf-1的siRNA转染上皮细胞和成纤维细胞。在此，我们证实APAF-1在两种细胞类型中被牙龈卟啉单胞菌靶向。本研究确定APAF-1溶酶体和XIAP是牙龈卟啉单胞菌的细胞内靶点，通过增加细菌在组织内的持久性和破坏宿主免疫反应而导致牙周病变的恶化。
Porphyromonas gingivalis is able to invade and modulate host-immune response to promote its survival. This bacterium modulates the cell cycle and programed cell death, contributing to periodontal lesion worsening. Several molecular pathways have been identified as key triggers of apoptosis, including apoptosome apoptotic peptidase activating factor 1 (APAF-1). Apaf-1 and X-linked inhibitor of apoptosis protein (Xiap) mRNA were differentially expressed between gingival samples harvested from human healthy and chronic periodontitis tissues (Apaf-1, 19.2-fold; caspase-9, 14.5-fold; caspase-3, 6.8-fold; Xiap: 2.5-fold in chronic periodontitis) (P < 0.05), highlighting their potential role in periodontitis. An increased proteic expression of APAF-1 was also observed in a murine experimental periodontitis model induced by P. gingivalis-soaked ligatures. In vitro, it was observed that P. gingivalis targets APAF-1, XIAP, caspase-3, and caspase-9, to inhibit epithelial cell death at both mRNA and protein levels. Opposite effect was observed in fibroblasts in which P. gingivalis increased cell death and apoptosis. To assess if the observed effects were associated to APAF-1, epithelial cells and fibroblasts were transfected with siRNA targeting Apaf-1. Herein, we confirmed that APAF-1 is targeted by P. gingivalis in both cell types. This study identified APAF-1 apoptosome and XIAP as intracellular targets of P. gingivalis, contributing to the deterioration of periodontal lesion through an increased persistence of the bacteria within tissues and the subversion of host-immune response.