Differential ER stress as a driver of cell fate following ricin toxin exposure.
Differential ER stress as a driver of cell fate following ricin toxin exposure.
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DOI：
10.1096/fba.2021-00005
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发表时间：
2022-01
影响因子：
2.7
通讯作者：
Mantis NJ
中科院分区：
文献类型：
--
作者：
Peterson-Reynolds C;Mantis NJ
吸入微量蓖麻毒素（一种植物来源的核糖体失活蛋白）可导致肺泡巨噬细胞消融、广泛上皮损伤和急性呼吸窘迫综合征（ARDS）发作。虽然蓖麻毒素受体普遍存在，但某些细胞类型对蓖麻毒素诱导的细胞死亡比其他细胞更敏感，原因尚不清楚。例如，我们在并行研究中证明，巨噬细胞样分化的THP-1（dTHP-1）细胞对蓖麻毒素高度敏感，而肺上皮来源的A549细胞相对不敏感，即使两种细胞类型在响应蓖麻毒素时经历相似程度的翻译抑制和p38 MAPK激活。使用各种小分子抑制剂，我们提供证据表明ER应激有助于蓖麻毒素介导的dTHP-1细胞的细胞毒性，但不是A549细胞。另一方面，A549细胞对蓖麻毒素的不敏感性通过加入（TNF）相关凋亡诱导配体（TRAIL; CD 253）克服，这是一种已知的外源性程序性细胞死亡刺激物。这些结果对于理解蓖麻毒素诱导的ARDS的复杂病理生理学具有意义，因为它们表明内在的（例如，ER应力）和外源性（例如，TRAIL）因子可能最终决定蓖麻毒素中毒后特定细胞类型的命运。
Inhalation of trace amounts of ricin toxin, a plant‐derived ribosome‐inactivating protein, results in ablation of alveolar macrophages, widespread epithelial damage, and the onset of acute respiratory distress syndrome (ARDS). While ricin's receptors are ubiquitous, certain cell types are more sensitive to ricin‐induced cell death than others for reasons that remain unclear. For example, we demonstrate in side‐by‐side studies that macrophage‐like differentiated THP‐1 (dTHP‐1) cells are hyper‐sensitive to ricin, while lung epithelium‐derived A549 cells are relatively insensitive, even though both cell types experience similar degrees of translational inhibition and p38 MAPK activation in response to ricin. Using a variety of small molecule inhibitors, we provide evidence that ER stress contributes to ricin‐mediated cytotoxicity of dTHP‐1 cells, but not A549 cells. On the other hand, the insensitivity of A549 cells to ricin was overcome by the addition of (TNF)‐related apoptosis‐inducing ligand (TRAIL; CD253), a known stimulator of extrinsic programmed cell death. These results have implications for understanding the complex pathophysiology of ricin‐induced ARDS in that they demonstrate that intrinsic (e.g., ER stress) and extrinsic (e.g., TRAIL) factors may ultimately determine the fate of specific cell types following ricin intoxication.
影响因子：
4.2
作者：
Gregers TF;Skånland SS;Wälchli S;Bakke O;Sandvig K
通讯作者：
Sandvig K