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A Critical Role for Hemolysins and Bacterial Lipoproteins in Staphylococcus aureus-Induced Activation of the Nlrp3 Inflammasome¹

Raúl Muñoz-Planillo^*, Luigi Franchi^*, Lloyd S. Miller and Gabriel Núñez^2,*

^* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109; and Division of Dermatology, University of California, Los Angeles, CA 90095

The mechanism by which bacterial pathogens activate caspase-1 via Nlrp3 remains poorly understood. In this study, we show that the ability of Staphylococcus aureus, a leading cause of infection in humans, to activate caspase-1 and induce IL-1β secretion resides in culture supernatants of growing bacteria. Caspase-1 activation induced by S. aureus required -, β-, and -hemolysins and the host Nlrp3 inflammasome. Mechanistically, - and β-hemolysins alone did not trigger caspase-1 activation, but they did so in the presence of bacterial lipoproteins released by S. aureus. Notably, caspase-1 activation induced by S. aureus supernatant was independent of the P2X7 receptor and the essential TLR adaptors MyD88 and TIR domain-containing adapter-inducing IFN-β, but was inhibited by extracellular K⁺. These results indicate that S. aureus hemolysins circumvent the requirement of ATP and the P2X7 receptor to induce caspase-1 activation via Nlrp3. Furthermore, these studies revealed that hemolysins promote in the presence of lipoproteins the activation of the Nlrp3 inflammasome.

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 This work was supported by Grants AI063331 and AI064748 (to G.N.). R.M.-P. was supported in part by a Fulbright-Ramón Areces Fellowship, and L.F. was supported by a fellowship grant from the Arthritis Foundation.

² Address correspondence and reprints request to Dr. Gabriel Núñez, Department of Pathology, University of Michigan Medical School, 4215 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu

³ Abbreviations used in this paper: NLR, nucleotide-binding oligomerization domain-like receptor; Asc, apoptosis-associated speck-like; P2X7R, P2X7 receptor; Trif, TIRdomain-containing adapter-inducing IFN-β; WT, wild type.

⁴ The online version of this article contains supplemental material.