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      Autophagy contributes to caspase-independent macrophage cell death.

      The Journal of Biological Chemistry

      metabolism, Animals, Apoptosis Regulatory Proteins, Autophagy, Caspases, Cell Death, Cell Survival, Chromatin, Lipopolysaccharides, chemistry, Macrophages, Mice, Models, Biological, Protein-Serine-Threonine Kinases, Proteins, pharmacology, Reactive Oxygen Species, Receptor-Interacting Protein Serine-Threonine Kinases, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Adaptor Proteins, Vesicular Transport

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          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.

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