Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line.
Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line.
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DOI：
10.3389/fcimb.2016.00182
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发表时间：
2016
影响因子：
5.7
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Cui Y;Zhao D;Sreevatsan S;Liu C;Yang W;Song Z;Yang L;Barrow P;Zhou X
牛分枝杆菌（M. bovis）高度适应巨噬细胞，并发展出多种机制来抵抗细胞内的攻击。然而，宿主细胞反过来会部署一种多管齐下的防御机制来控制细菌感染。内质网（ER）应激介导的细胞凋亡就是这样一种主要的防御机制。然而，在牛分枝杆菌感染过程中，干扰素调节因子3（IRF3）在内质网应激和细胞凋亡之间的作用尚不清楚。在此，我们证明牛分枝杆菌能有效诱导小鼠巨噬细胞凋亡。在48小时的感染期间，半胱天冬酶 - 12、半胱天冬酶 - 9和半胱天冬酶 - 3被激活。XBP - 1 mRNA的剪接以及eIF2α的磷酸化水平（内质网应激的指标）在牛分枝杆菌感染后的早期时间点显著增加。内质网腔室的扩张（内质网应激的一种形态学特征）在6小时时被观察到。用4 - PBA（一种内质网应激抑制剂）预处理Raw 264.7细胞可降低内质网应激指标的激活、半胱天冬酶的激活及其下游的多聚（ADP - 核糖）聚合酶（PARP）的裂解、TBK1和IRF3的磷酸化以及STING和TBK1的细胞质共定位。牛分枝杆菌感染导致活化的IRF3与细胞质中的Bax相互作用，从而导致线粒体损伤。通过用BX - 795阻断该分子进一步证实了IRF3在细胞凋亡中的作用，BX - 795显示半胱天冬酶 - 8和半胱天冬酶 - 3的表达显著降低。牛分枝杆菌的细胞内存活率在4 - PBA和BX - 795作用下增加。这些发现表明，在牛分枝杆菌感染过程中，STING - TBK1 - IRF3通路介导内质网应激和细胞凋亡之间的相互作用，从而能有效控制细胞内细菌。
Mycobacterium bovis (M. bovis) is highly adapted to macrophages and has developed multiple mechanisms to resist intracellular assaults. However, the host cells in turn deploy a multipronged defense mechanism to control bacterial infection. Endoplasmic reticulum (ER) stress-mediated apoptosis is one such primary defense mechanism. However, the role of interferon regulatory factor 3 (IRF3) between ER stress and apoptosis during M. bovis infection is unknown. Here, we demonstrate that M. bovis effectively induced apoptosis in murine macrophages. Caspase-12, caspase-9, and caspase-3 were activated over a 48 h infection period. The splicing of XBP-1 mRNA and the level of phosphorylation of eIF2α, indicators of ER stress, significantly increased at early time points after M. bovis infection. The expansion of the ER compartment, a morphological hallmark of ER stress, was observed at 6 h. Pre-treatment of Raw 264.7 cells with 4-PBA (an ER stress-inhibitor) reduced the activation of the ER stress indicators, caspase activation and its downstream poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylation of TBK1 and IRF3 and cytoplasmic co-localization of STING and TBK1. M. bovis infection led to the interaction of activated IRF3 and cytoplasmic Bax leading to mitochondrial damage. Role of IRF3 in apoptosis was further confirmed by blocking this molecule with BX-795 that showed significant reduction expression of caspase-8 and caspase-3. Intracellular survival of M. bovis increased in response to 4-PBA and BX-795. These findings indicate that STING-TBK1-IRF3 pathway mediates a crosstalk between ER stress and apoptosis during M. bovis infection, which can effectively control intracellular bacteria.
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