Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin.
Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin.
Am J Pathol. 2020 Feb;190(2):272-285. doi: 10.1016/j.ajpath.2019.10.012. Epub 2019 Nov 26.
Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be crucial during pathologic evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in preclinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programed cell death in the clinic.
在过去的 15 年中，一系列精巧的研究表明，在某些条件下，细胞程序性死亡类似于细胞坏死，并依赖于一种独特的分子途径，与细胞凋亡无重叠。这种形式的调节性细胞坏死被称为坏死性凋亡，其中受体相互作用蛋白激酶 3 和其底物混合谱系激酶结构域样蛋白起着至关重要的作用。随着敲除小鼠模型和坏死性蛋白特有的分子抑制剂的发展，这种细胞死亡已在评估的几乎所有组织和疾病中被发现。细胞通过凋亡或坏死性凋亡而死亡会产生不同的免疫后果。因此，在病理评估过程中区分这两种形式的细胞死亡可能至关重要。在这篇综述中，我们对坏死性细胞死亡有了一定的了解，并强调了坏死性凋亡在哪些疾病中发挥作用。我们还讨论了坏死性凋亡的抑制剂以及这些抑制剂在疾病的临床前模型中的应用。这两个讨论有助于理解坏死性凋亡在疾病中的作用，并将促进在临床上靶向这种独特而普遍的程序性细胞死亡形式的努力。
