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Pure Hemozoin Is Inflammatory In Vivo and Activates the NALP3 Inflammasome via Release of Uric Acid¹

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511

The role of proinflammatory cytokine production in the pathogenesis of malaria is well established, but the identification of the parasite products that initiate inflammation is not complete. Hemozoin is a crystalline metabolite of hemoglobin digestion that is released during malaria infection. In the present study, we characterized the immunostimulatory activity of pure synthetic hemozoin (sHz) in vitro and in vivo. Stimulation of naive murine macrophages with sHz results in the MyD88-independent activation of NF-B and ERK, as well as the release of the chemokine MCP-1; these responses are augmented by IFN-. In macrophages prestimulated with IFN-, sHz also results in a MyD88-dependent release of TNF-. Endothelial cells, which encounter hemozoin after schizont rupture, respond to sHz by releasing IL-6 and the chemokines MCP-1 and IL-8. In vivo, the introduction of sHz into the peritoneal cavity produces an inflammatory response characterized by neutrophil recruitment and the production of MCP-1, KC, IL-6, IL-1, and IL-1β. MCP-1 and KC are produced independently of MyD88, TLR2/4 and TLR9, and components of the inflammasome; however, neutrophil recruitment, the localized production of IL-1β, and the increase in circulating IL-6 require MyD88 signaling, the IL-1R pathway, and the inflammasome components ICE (IL-1β-converting enzyme), ASC (apoptosis-associated, speck-like protein containing CARD), and NALP3. Of note, inflammasome activation by sHz is reduced by allopurinol, which is an inhibitor of uric acid synthesis. These data suggest that uric acid is released during malaria infection and may serve to augment the initial host response to hemozoin via activation of the NALP3 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 National Institutes of Health Grants AI051306, AI042310-07 (to R.B.), MSTP TG 5T32GM07205 (to J.W.G.), a Predoctoral NIH Training Grant in Microbial Pathogenesis T32 AI007640-06A1 (to T.S.), and a fellowship from the National Science Foundation (to T.S.).

² Address correspondence and reprint requests to Dr. Richard Bucala, Yale University, 300 Cedar Street, TAC S525, P.O. Box 208031, New Haven, CT 06520. E-mail address: Richard.Bucala{at}Yale.edu

³ Abbreviations used in this paper: ASC, apoptosis-associated, speck-like protein containing CARD; FL-DC, FLT-3 ligand-derived mouse dendritic cell; DC, dendritic cell; ICE, IL-1β-converting enzyme; IPAF, IL-1β-converting enzyme protease activating factor; NLR, nucleotide-binding domain leucine-rich repeat; sHz, synthetic hemozoin; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β; WT, wild type.