Chautan M, Chazal G, Cecconi F, Gruss P, Golstein P
Centre d'Immunologie INSERM-CNRS de Marseille-Luminy Case 906, 13288, Marseille, Cedex 9, France.
Curr Biol. 1999 Sep 9;9(17):967-70. doi: 10.1016/s0960-9822(99)80425-4.
Programmed cell death in animals is usually associated with apoptotic morphology and requires caspase activation. Necrosis and caspase-independent cell death have been reported, but mostly in experimental conditions that lead some to question their existence it in vivo. Loss of interdigital cells in the mouse embryo, a paradigm of cell death during development [1], is known to include an apoptotic [2] and caspase-dependent [3] [4] mechanism. Here, we report that, when caspase activity was inhibited using drugs or when apoptosis was prevented genetically (using Hammertoe mutant mice, or mice homozygous for a mutation in the gene encoding APAF-1, a caspase-activating adaptor protein), interdigital cell death still occurred. This cell death was negative for the terminal-deoxynucleotidyl-mediated dUTP nick end-labelling (TUNEL) assay and there was no overall cell condensation. At the electron microscopy level, peculiar 'mottled' chromatin alterations and marked mitochondrial and membrane lesions, suggestive of classical necrotic cell death, were observed with no detectable phagocytosis and no local inflammatory response. Thus, in this developmental context, although caspase activity confers cell death with an apoptotic morphotype, in the absence of caspase activity an underlying mechanism independent of known caspases can also confer cell death, but with a necrotic morphotype. This cell death can go undetected when using apoptosis-specific methodology, and cannot be blocked by agents that act on caspases.
动物体内的程序性细胞死亡通常与凋亡形态相关，且需要半胱天冬酶激活。虽然已有坏死和非半胱天冬酶依赖性细胞死亡的报道，但大多是在一些实验条件下，这使得一些人质疑它们在体内的存在。小鼠胚胎中趾间细胞的缺失是发育过程中细胞死亡的一个范例[1]，已知其涉及凋亡[2]和半胱天冬酶依赖性[3][4]机制。在此，我们报告，当使用药物抑制半胱天冬酶活性或通过基因手段阻止凋亡时（使用锤状趾突变小鼠，或编码半胱天冬酶激活衔接蛋白APAF-1的基因突变的纯合小鼠），趾间细胞死亡仍会发生。这种细胞死亡在末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）检测中呈阴性，且没有整体细胞凝聚现象。在电子显微镜水平上，观察到了特殊的“斑驳状”染色质改变以及明显的线粒体和膜损伤，提示典型的坏死性细胞死亡，未检测到吞噬作用，也没有局部炎症反应。因此，在这种发育背景下，虽然半胱天冬酶活性赋予细胞死亡以凋亡形态，但在缺乏半胱天冬酶活性时，一种独立于已知半胱天冬酶的潜在机制也可导致细胞死亡，但具有坏死形态。当使用凋亡特异性方法时，这种细胞死亡可能无法被检测到，并且不能被作用于半胱天冬酶的药物所阻断。
