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J. Biol. Chem., Vol. 281, Issue 28, 19179-19187, July 14, 2006

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Autophagy Contributes to Caspase-independent Macrophage Cell Death^*

Yue Xu, Sung Ouk Kim, Yilei Li, and Jiahuai Han¹

From the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037 and the Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G 2B4, Canada

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- (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.

Received for publication, December 15, 2005 , and in revised form, March 21, 2006.

^* This work was supported in part by National Institutes of Health Grant GM67101. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Immunology, The Scripps Research Institute, 10550 North Torrey Pines, La Jolla, CA 92037. E-mail: jhan{at}scripps.edu.

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