Salmonella induces macrophage death by caspase-1-dependent necrosis
Salmonella induces macrophage death by caspase-1-dependent necrosis
复制标题
DOI：
10.1046/j.1365-2958.2000.02103.x
复制
发表时间：
2000-10-01
影响因子：
3.6
通讯作者：
Cookson, BT
中科院分区：
文献类型：
--
作者：
Brennan, MA;Cookson, BT
我们提供的证据表明，鼠伤寒沙门氏菌杀死吞噬细胞的一个不寻常的促炎机制的坏死，是从细胞凋亡的区别。感染刺激了一个明显的弥漫性模式的DNA片段在巨噬细胞中，这与显着的核浓缩显示的控制细胞进行化学诱导的凋亡，在凋亡细胞中，DNA片段化和核浓缩的结果从半胱天冬酶3介导的蛋白水解，半胱天冬酶也颠覆了坏死性细胞死亡的裂解和失活聚ADP-核糖聚合酶（PARP）。Caspase-3在沙门氏菌感染过程中未被激活，PARP仍处于活性未裂解状态。细胞凋亡的另一个标志是细胞死亡期间持续的膜完整性;然而，感染的巨噬细胞迅速失去膜完整性，如通过同时暴露磷脂酰丝氨酸与摄取活体染料和释放细胞质酶乳酸脱氢酶所示。在实验诱导的坏死，通过质膜的致死离子通量可以防止外源性甘氨酸;同样，甘氨酸完全阻断沙门氏菌诱导的细胞毒性。最后，抑制白细胞介素（IL）-1-转化酶半胱天冬酶-1阻断感染的巨噬细胞的死亡，但不控制细胞诱导进行凋亡或坏死。因此，沙门氏菌感染的巨噬细胞被一种不寻常的半胱天冬酶-1依赖性坏死机制杀死。
We provide evidence that Salmonella typhimurium kills phagocytes by an unusual proinflammatory mechanism of necrosis that is distinguishable from apoptosis. Infection stimulated a distinctly diffuse pattern of DNA fragmentation in macrophages, which contrasted with the marked nuclear condensation displayed by control cells undergoing chemically induced apoptosis, In apoptotic cells, DNA fragmentation and nuclear condensation result from caspase-3-mediated proteolysis; caspases also subvert necrotic cell death by cleaving and inactivating poly ADP-ribose polymerase (PARP). Caspase-3 was not activated during Salmonella infection, and PARP remained in its active, uncleaved state. Another hallmark of apoptosis is sustained membrane integrity during cell death; yet, infected macrophages rapidly lost membrane integrity, as indicated by simultaneous exposure of phosphatidylserine with the uptake of vital dye and the release of the cytoplasmic enzyme lactate dehydrogenase. During experimentally induced necrosis, lethal ion fluxes through the plasma membrane can be prevented by exogenous glycine; similarly, glycine completely blocked Salmonella-induced cytotoxicity. Finally, inhibition of the interleukin (IL)-1-converting enzyme caspase-1 blocked the death of infected macrophages, but not control cells induced to undergo apoptosis or necrosis. Thus, Salmonella-infected macrophages are killed by an unusual caspase-1-dependent mechanism of necrosis.