Abstract
The intraerythrocytic parasite Plasmodium -- the causative agent of malaria -- produces an inorganic crystal called hemozoin (Hz) during the heme detoxification process, which is released into the circulation during erythrocyte lysis. Hz is rapidly ingested by phagocytes and induces the production of several pro-inflammatory mediators such as interleukin-1beta (IL-1beta). However, the mechanism regulating Hz recognition and IL-1beta maturation has not been identified. Here, we show that Hz induces IL-1beta production. Using knockout mice, we showed that Hz-induced IL-1beta and inflammation are dependent on NOD-like receptor containing pyrin domain 3 (NLRP3), ASC and caspase-1, but not NLRC4 (NLR containing CARD domain). Furthermore, the absence of NLRP3 or IL-1beta augmented survival to malaria caused by P. chabaudi adami DS. Although much has been discovered regarding the NLRP3 inflammasome induction, the mechanism whereby this intracellular multimolecular complex is activated remains unclear. We further demonstrate, using pharmacological and genetic intervention, that the tyrosine kinases Syk and Lyn play a critical role in activation of this inflammasome. These findings not only identify one way by which the immune system is alerted to malarial infection but also are one of the first to suggest a role for tyrosine kinase signaling pathways in regulation of the NLRP3 inflammasome.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / immunology
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Apoptosis Regulatory Proteins / metabolism
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins / immunology
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Calcium-Binding Proteins / metabolism
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Caspase 1 / immunology
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Caspase 1 / metabolism
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Cathepsin B / metabolism
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Cytoskeletal Proteins / immunology
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Cytoskeletal Proteins / metabolism
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Disease Models, Animal
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Female
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HSP90 Heat-Shock Proteins / metabolism
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Hemeproteins / immunology
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Hemeproteins / metabolism
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Hemeproteins / physiology*
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Humans
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Inflammation / immunology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism*
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Malaria / immunology
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Malaria / metabolism
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Malaria / parasitology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NLR Family, Pyrin Domain-Containing 3 Protein
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Neutrophil Infiltration / immunology
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Phagocytosis
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Phosphorylation / immunology
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Plasmodium chabaudi / chemistry
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Plasmodium chabaudi / metabolism
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Potassium / metabolism
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Protein-Tyrosine Kinases / metabolism*
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Proteomics
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Reactive Oxygen Species / metabolism
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Signal Transduction / immunology
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Syk Kinase
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src-Family Kinases / metabolism*
Substances
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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HSP90 Heat-Shock Proteins
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Hemeproteins
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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Ipaf protein, mouse
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Pycard protein, mouse
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Reactive Oxygen Species
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hemozoin
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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lyn protein-tyrosine kinase
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src-Family Kinases
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Cathepsin B
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Ctsb protein, mouse
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Caspase 1
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Potassium