Autophagy contributes to caspase-independent macrophage cell death
Autophagy contributes to caspase-independent macrophage cell death
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DOI：
10.1074/jbc.m513377200
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发表时间：
2006-07-14
影响因子：
4.8
通讯作者：
Han, Jiahuai
中科院分区：
文献类型：
--
作者：
Xu, Yue;Kim, Sung Ouk;Han, Jiahuai
巨噬细胞死亡在许多生理和病理生理状态中起着重要作用。先前的工作表明，巨噬细胞可以经历caspase非依赖性的细胞死亡，这一过程与Nur77的诱导有关，Nur77参与诱导染色质凝聚和DNA片段化。在这里，我们发现自噬是一种控制caspase非依赖性巨噬细胞死亡的胞浆事件。用脂多糖(LPSs)和泛半胱氨酸氨基转移酶抑制剂(Z-VAD)诱导巨噬细胞自噬，化学抑制剂或RNA干扰敲除Beclin(自噬小体形成所必需的蛋白质)抑制自噬，可抑制caspase非依赖性的巨噬细胞死亡。我们还发现，在LPS+Z-VAD处理的巨噬细胞中，聚腺苷二磷酸核糖(PAR)聚合酶(PARP)活性和活性氧(ROS)产生增加，两者都参与了caspase非依赖性巨噬细胞的死亡。我们进一步确定，巨噬细胞中自噬小体的形成发生在PARP激活的下游，PARP的激活发生在ROS产生的下游。利用受体相互作用蛋白1(RIP1)被小干扰RNA敲除的巨噬细胞和从Toll/IL-1受体结构域适配器分离的诱导干扰素-β(TRIF)缺陷小鼠的巨噬细胞，我们发现TRIF和RIP1在LPS+Z-VAD处理的巨噬细胞中作用于ROS产生的上游。我们还发现，Z-VAD抑制了内毒素诱导的RIP1裂解，这可能是导致巨噬细胞ROS过度产生的原因之一。本文揭示了TRIF、RIP1和ROS的产生，以及PARP的激活，参与了诱导自噬，这有助于caspase非依赖的巨噬细胞死亡。
Macrophage cell death plays a role in many physiological and pathophysiological conditions. Previous work has shown that macrophages can undergo caspase-independent cell death, and this process is associated with Nur77 induction, which is involved in inducing chromatin condensation and DNA fragmentation. Here we show that autophagy is a cytosolic event that controls caspase-independent macrophage cell death. Autophagy was induced in macrophages treated with lipopolysaccharides (LPSs) and the pan- caspase inhibitor benzyloxycarbonyl-Val- Ala-Asp (Z-VAD), and the inhibition of autophagy by either chemical inhibitors or by the RNA interference knockdown of beclin (a protein required for autophagic body formation) inhibited caspase-independent macrophage cell death. We also found an increase in poly(ADP-ribose) (PAR) polymerase (PARP) activation and reactive oxygen species (ROS) production in LPS + Z-VAD-treated macrophages, and both are involved in caspase-independent macrophage cell death. We further determined that the formation of autophagic bodies in macrophages occurs downstream of PARP activation, and PARP activation occurs downstream of ROS production. Using macrophages in which receptor-interacting protein 1 (RIP1) was knocked down by small interfering RNA, and macrophages isolated from Toll/ interleukin-1 receptor-domain-containing adaptor inducing IFN-beta (TRIF)-deficient mice, we found that TRIF and RIP1 function upstream of ROS production in LPS + Z-VAD-treated macrophages. We also found that Z-VAD inhibits LPS-induced RIP1 cleavage, which may contribute to ROS over-production in macrophages. This paper reveals that TRIF, RIP1, and ROS production, as well as PARP activation, are involved in inducing autophagy, which contributes to caspase-independent macrophage cell death.