Malarial Hemozoin Activates the NLRP3 Inflammasome through Lyn and Syk Kinases

PLoS Pathogens

Richard A. Flavell¹  Fayyaz S. Sutterwala¹  Stephanie C. Eisenbarth²  Myriam Savaria³  Adrien F. Vinet⁴  Kenneth W. Harder⁴  Marina Tiemi Shio⁴  D. Scott Bohle⁵  Albert Descoteaux⁶  Marie-Josée Bellemare⁷  Martin Olivier⁷ 

[1] Department of Chemistry, McGill University, Montréal, Quebec, Canada;Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America;Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America;Department of Medicine, Microbiology and Immunology, Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada;Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada;Inflammation Program, Department of Medicine, University of Iowa, Iowa City, Iowa, United States of America;Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, Quebec, Canada

关键词: Inflammasomes;    Malaria;    Phosphorylation;    Immune receptor signaling;    Macrophages;    Neutrophils;    Immunoprecipitation;    Crystals;   

DOI  :  10.1371/journal.ppat.1000559

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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

【 授权许可】

CC BY