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J. Biol. Chem., Vol. 281, Issue 48, 36560-36568, December 1, 2006

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Critical Role for Cryopyrin/Nalp3 in Activation of Caspase-1 in Response to Viral Infection and Double-stranded RNA^*>

Thirumala-Devi Kanneganti¹, Mathilde Body-Malapel², Amal Amer, Jong-Hwan Park, Joel Whitfield, Luigi Franchi, Zenobia F. Taraporewala³, David Miller^¶, John T. Patton³, Naohiro Inohara, and Gabriel Núñez⁴

From the Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and ^¶Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Viral infection induces the production of interleukin (IL)-1 and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1 and IL-18 in a cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the cryopyrin inflammasome. Finally, cryopyrin was required for IL-1 production in response to poly(I:C) in vivo. These results identify a mechanism mediated by cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1 and IL-18 production.

Received for publication, August 9, 2006 , and in revised form, September 20, 2006.

^* This work was supported in part by National Institutes of Health Grants AI063331 and AI064748 (to G. N.). 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 supplemental Fig. 1.

¹ Supported by National Institutes of Health Training Grant 5/T32/HL007517.

² Supported by a postdoctoral fellowship from the Center for Genetics in Health and Medicine at the University of Michigan.

³ Supported by the Intramural Research Program of the NIAID, National Institutes of Health.

⁴ To whom correspondence should be addressed: Dept. of Pathology, University of Michigan Medical School, 4215 CCGC, 1500 E. Medical Ctr. Dr., Ann Arbor, MI 48109. Tel.: 734-764-8514; Fax: 734-647-9654; E-mail: bclx{at}umich.edu.

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