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Papers In Press, published online ahead of print May 15, 2006
The Scripps Research Institute, La Jolla, CA 92037
Corresponding Author: jhan{at}scripps.edu
Macrophage cell death plays a role in many physiological and patho-physiological conditions. Previous works have 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 (LPS) and the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (zVAD), and the inhibition of autophagy by either chemical inhibitors or by the RNAi 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+zVAD-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 siRNA, and macrophages isolated from Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-beta (TRIF) deficient mice, we found that TRIF and RIP1 function upstream of ROS production in LPS+zVAD-treated macrophages. We also found that zVAD 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.
J. Biol. Chem, 10.1074/jbc.M513377200
Submitted on December 15, 2005
Revised on March 21, 2006
Accepted on May 15, 2006
Autophagy contributes to caspase-independent macrophage cell death
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