Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid.
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-kappaB and ERK, as well as the release of the chemokine MCP-1; these responses are augmented by IFN-gamma. In macrophages prestimulated with IFN-gamma, sHz also results in a MyD88-dependent release of TNF-alpha. 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-1alpha, and IL-1beta. 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-1beta, and the increase in circulating IL-6 require MyD88 signaling, the IL-1R pathway, and the inflammasome components ICE (IL-1beta-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.
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
Jason W
JW
Griffith
Tiffany
T
Sun
Michael T
MT
McIntosh
Richard
R
Bucala
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006420:Hemeproteins / Q000276:immunology* / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000469:parasitology*; D007371:Interferon-gamma / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010963:Plasmodium falciparum; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014527:Uric Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D003598:Cytoskeletal Proteins; D006420:Hemeproteins; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid; C020753:hemozoin; D000493:Allopurinol; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases