Department of Medical Education, University of Melbourne, Parkville, VIC 3052, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Biomolecules. 2021 May 28;11(6):803. doi: 10.3390/biom11060803.
Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein-MLKL-shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL's contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies.
细胞程序性坏死是一种炎症形式的细胞溶解死亡，被认为是进化来防御病原体的。在常规实验室饲养条件下，C57BL/6 小鼠品系中末端效应蛋白-MLKL 的基因缺失并没有明显的表型。通过靶向 RIPK1 的激酶活性抑制细胞程序性坏死的小分子，这些小分子是 MLKL 激活的主要上游通路之一，在几种非传染性疾病的小鼠模型和 II 期人类临床试验中显示出了希望。这引发了超过 10 亿美元的投资进入新兴的细胞程序性坏死阻断药物领域，并且正在密切关注靶向末端效应的潜在效用。在这里，我们回顾了疾病的小鼠模型，包括基因缺失和突变，以研究 MLKL 的作用。我们总结了来自几个广泛疾病类别的一系列例子，包括缺血再灌注损伤、无菌性炎症、病原体感染和血液应激。阐明 MLKL 在疾病小鼠模型中的作用是确定最有可能受益于 MLKL 靶向药物治疗的人类适应症的重要第一步。
