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Infection and Immunity, March 2009, p. 1262-1271, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01032-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Anthrax Lethal Toxin Triggers the Formation of a Membrane-Associated Inflammasome Complex in Murine Macrophages{triangledown}

Adel M. Nour,1 Yee-Guide Yeung,2 Laura Santambrogio,3 Eric D. Boyden,4 E. Richard Stanley,2 and Jürgen Brojatsch1*

Department of Microbiology and Immunology,1 Department of Developmental and Molecular Biology,2 Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461,3 Department of Orthopedics, Children's Hospital Boston, Boston, Massachusetts 021154

Received 19 August 2008/ Returned for modification 17 September 2008/ Accepted 23 December 2008

Multiple microbial components trigger the formation of an inflammasome complex that contains pathogen-specific nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs), caspase-1, and in some cases the scaffolding protein ASC. The NLR protein Nalp1b has been linked to anthrax lethal toxin (LT)-mediated cytolysis of murine macrophages. Here we demonstrate that in unstimulated J774A.1 macrophages, caspase-1 and Nalp1b are membrane associated and part of ~200- and ~800-kDa complexes, respectively. LT treatment of these cells resulted in caspase-1 recruitment to the Nalp1b-containing complex, concurrent with processing of cytosolic caspase-1 substrates. We further demonstrated that Nalp1b and caspase-1 are able to interact with each other. Intriguingly, both caspase-1 and Nalp1b were membrane associated, while the caspase-1 substrate interleukin-18 was cytosolic. Caspase-1-associated inflammasome components included, besides Nalp1b, proinflammatory caspase-11 and the caspase-1 substrate {alpha}-enolase. Asc was not part of the Nalp1b inflammasome in LT-treated macrophages. Taken together, our findings suggest that LT triggers the formation of a membrane-associated inflammasome complex in murine macrophages, resulting in cleavage of cytosolic caspase-1 substrates and cell death.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Golding 404, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-3079. Fax: (718) 430-8711. E-mail: brojatsc{at}aecom.yu.edu

{triangledown} Published ahead of print on 5 January 2009.

Editor: J. B. Bliska

Infection and Immunity, March 2009, p. 1262-1271, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01032-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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