Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL.
Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL.
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作者：
Hao Q;Shetty S;Tucker TA;Idell S;Tang H
坏死性下垂是细胞程序性死亡的一种形式，已成为急性肺损伤(ALI)发病的驱动因素。由于ALI通常与细胞因子风暴有关，我们确定了促炎细胞因子是否调节了肺细胞对坏死性下垂的易感性，以及哪些介质在控制坏死性下垂方面起主导作用。在这项研究中，我们用不同的炎症介质对小鼠原代肺上皮细胞和内皮细胞进行预处理，并评估了不同的坏死性下垂诱导剂对细胞类型的依赖反应及其潜在机制。我们发现，低至1 ng/mL的干扰素-γ(γ)优先促进坏死性下垂，并加速原代肺泡和呼吸道上皮细胞释放损伤相关的分子模式，但不包括肺微血管内皮细胞。I型干扰素α的疗效约为干扰素γ的50倍。相反，肿瘤坏死因子α或Toll样受体-3、TLR4、TLR7和TLR9激动剂的作用较小。干扰素γ激活的肺上皮细胞坏死性下垂的增强依赖于干扰素γ信号和受体相互作用蛋白激酶-3。我们进一步证明，干扰素γ主要诱导坏死性下垂效应分子混合谱系蛋白样蛋白表达，从而导致肺上皮细胞坏死性下垂的增强。总之，我们的研究结果表明，干扰素γ是一种有效的肺上皮细胞对坏死性下垂易感性的增强剂。
Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury (ALI). As ALI is often associated with a cytokine storm, we determined whether pro-inflammatory cytokines modulate the susceptibility of lung cells to necroptosis and which mediators dominate to control necroptosis. In this study, we pretreated/primed mouse primary lung epithelial and endothelial cells with various inflammatory mediators and assessed cell type-dependent responses to different necroptosis inducers and their underlying mechanisms. We found that interferon-γ (IFNγ) as low as 1 ng/mL preferentially promoted necroptosis and accelerated the release of damage-associated molecular patterns from primary alveolar and airway epithelial cells but not lung microvascular endothelial cells. Type-I IFNα was about fifty-fold less effective than IFNγ. Conversely, TNFα or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFNγ-activated lung epithelial cells was dependent on IFNγ signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFNγ, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFNγ is a potent enhancer of lung epithelial cell susceptibility to necroptosis.
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