Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases

Marina Tiemi Shio*, Stephanie C. Eisenbarth, Myriam Savaria, Adrien F. Vinet, Marie Josée Bellemare, Kenneth W. Harder, Fayyaz S. Sutterwala, D. Scott Bohle, Albert Descoteaux, Richard A. Flavell, Martin Olivier

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

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-1b (IL-1b). However, the mechanism regulating Hz recognition and IL-1b maturation has not been identified. Here, we show that Hz induces IL-1b production. Using knockout mice, we showed that Hz-induced IL-1b 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-1b 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.

Original languageEnglish (US)
Article numbere1000559
JournalPLoS pathogens
Volume5
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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