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J. Biol. Chem., Vol. 280, Issue 14, 14042-14050, April 8, 2005

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A Novel Caspase-1/Toll-like Receptor 4-independent Pathway of Cell Death Induced by Cytosolic Shigella in Infected Macrophages^*

Toshihiko Suzuki¶, Kenji Nakanishi||**, Hiroko Tsutsui||**, Hiroki Iwai, Shizuo Akira, Naohiro Inohara¶¶, Mathias Chamaillard¶¶||||, Gabriel Nuñez¶¶||||, and Chihiro Sasakawa**

From the Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, the ^||Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, 663-8501, Japan, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita, Osaka 565-0871, Japan, the ^¶¶Department of Pathology and ^||||Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, and PRESTO, ^**CREST, and Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan

Shigella-induced macrophage cell death is an important step in the induction of acute inflammatory responses that ultimately lead to bacillary dysentery. Cell death was previously reported to be dependent upon the activation of caspase-1 via interaction with IpaB secreted by intracellular Shigella, but in this study, we show that Shigella infection of macrophages can also induce cell death independent of caspase-1 or IpaB activity. Time-lapse imaging and electron microscopic analyses indicated that caspase-1-dependent and -independent cell death is morphologically indistinguishable and that both resemble necrosis. Analyses of Shigella mutants or Escherichia coli using co-infection with Listeria suggested that a component common to Gram-negative bacteria is involved in inducing caspase-1-independent cell death. Further studies revealed that translocation of bacterial lipid A into the cytosol of macrophages potentially mediates cell death. Notably, cell death induced by cytosolic bacteria was TLR4-independent. These results identify a novel cell death pathway induced by intracellular Gram-negative bacteria that may play a role in microbial-host interactions and inflammatory responses.

Received for publication, December 30, 2004 , and in revised form, February 1, 2005.

^* This work was supported by Japan Science and Technology Agency and by a grant-in-aid for scientific research from the Japanese Ministry of Education, Culture, Sports, and Technology. 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.

The on-line version of this article (available at http://www.jbc.org) contains a four supplementary movies related to Figs. 2 and 3.

^¶ To whom correspondence should be addressed. Tel.: 81-3-5449-5253; Fax: 81-3-5449-5250; E-mail: t-suzuki{at}ims.u-tokyo.ac.jp.

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