title: Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases.
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.
authors.affiliation: 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.
authors.forename: Marina Tiemi
authors.initials: MT
authors.lastname: Shio
authors.forename: Marina
authors.initials: M
authors.lastname: Tiemi Shio
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Myriam
authors.initials: M
authors.lastname: Savaria
authors.forename: Adrien F
authors.initials: AF
authors.lastname: Vinet
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Bellemare
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Harder
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.forename: D Scott
authors.initials: DS
authors.lastname: Bohle
authors.forename: Albert
authors.initials: A
authors.lastname: Descoteaux
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006420:Hemeproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008288:Malaria / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000276:immunology; D010587:Phagocytosis; D010766:Phosphorylation / Q000276:immunology; D016788:Plasmodium chabaudi / Q000737:chemistry / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018841:HSP90 Heat-Shock Proteins; D006420:Hemeproteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; C020753:hemozoin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D020170:Caspase 1; D011188:Potassium
references.citation: Nature. 1992 Apr 30;356(6372):768-74
references.pmid: 1574116
references.citation: Immunity. 2008 Nov 14;29(5):807-18
references.pmid: 18993083
references.citation: Immunol Lett. 2006 Apr 15;104(1-2):29-37
references.pmid: 16332394
references.citation: Nature. 2004 Jul 8;430(6996):213-8
references.pmid: 15190255
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13501-6
references.pmid: 14595024
references.citation: J Cell Sci. 2006 Feb 15;119(Pt 4):605-14
references.pmid: 16467569
references.citation: J Immunol. 2003 Oct 15;171(8):4243-53
references.pmid: 14530348
references.citation: Mol Cell. 2002 Aug;10(2):417-26
references.pmid: 12191486
references.citation: Nat Clin Pract Rheumatol. 2008 Jan;4(1):34-42
references.pmid: 18172447
references.citation: Curr Opin Immunol. 2008 Aug;20(4):377-82
references.pmid: 18585455
references.citation: Nat Immunol. 2006 Jun;7(6):576-82
references.pmid: 16648852
references.citation: Cell Host Microbe. 2008 Sep 11;4(3):198-208
references.pmid: 18779046
references.citation: Immunity. 1999 Jul;11(1):115-22
references.pmid: 10435584
references.citation: Am J Trop Med Hyg. 2002 May;66(5):458-60
references.pmid: 12201576
references.citation: Mol Cell. 2007 Oct 26;28(2):214-27
references.pmid: 17964261
references.citation: J Biol Chem. 1987 Nov 15;262(32):15552-5
references.pmid: 3119578
references.citation: Immunol Rev. 2007 Oct;219:75-87
references.pmid: 17850483
references.citation: Structure. 2003 Oct;11(10):1199-205
references.pmid: 14527388
references.citation: Nature. 2009 May 21;459(7245):433-6
references.pmid: 19339971
references.citation: Curr Biol. 2007 Jul 3;17(13):1140-5
references.pmid: 17600714
references.citation: J Immunol. 2005 Jan 1;174(1):475-84
references.pmid: 15611273
references.citation: Nat Immunol. 2008 Aug;9(8):847-56
references.pmid: 18604214
references.citation: EMBO J. 2008 May 7;27(9):1333-44
references.pmid: 18369315
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1919-24
references.pmid: 17261807
references.citation: J Exp Med. 2006 Jun 12;203(6):1407-12
references.pmid: 16717117
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9035-40
references.pmid: 18577586
references.citation: Nat Rev Immunol. 2005 Sep;5(9):722-35
references.pmid: 16138104
references.citation: Nature. 2006 Mar 9;440(7081):237-41
references.pmid: 16407889
references.citation: Genes Cells. 2005 Jan;10(1):23-35
references.pmid: 15670211
references.citation: Immunity. 1995 Jul;3(1):9-19
references.pmid: 7621081
references.citation: J Immunol. 2004 Mar 1;172(5):3101-10
references.pmid: 14978116
references.citation: Immunity. 2006 Mar;24(3):317-27
references.pmid: 16546100
references.citation: Int Immunol. 2007 Jan;19(1):67-79
references.pmid: 17135446
references.citation: Nature. 2006 Mar 9;440(7081):228-32
references.pmid: 16407890
references.citation: Mol Biosyst. 2008 May;4(5):380-6
references.pmid: 18414735
references.citation: Biochem J. 2003 Jul 1;373(Pt 1):101-13
references.pmid: 12656673
references.citation: Cell Death Differ. 2003 Sep;10(9):956-68
references.pmid: 12934070
references.citation: Immunity. 2001 Oct;15(4):603-15
references.pmid: 11672542
references.citation: Nature. 2008 Jun 19;453(7198):1122-6
references.pmid: 18496530
references.citation: J Immunol. 2008 Oct 15;181(8):5289-95
references.pmid: 18832684
references.citation: Science. 1995 Mar 31;267(5206):2000-3
references.pmid: 7535475
references.citation: J Immunol. 2007 Aug 1;179(3):1913-25
references.pmid: 17641058
references.citation: Am J Physiol Cell Physiol. 2004 May;286(5):C1100-8
references.pmid: 15075209
references.citation: Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5111-3
references.pmid: 2052590
references.citation: Nat Immunol. 2007 May;8(5):497-503
references.pmid: 17435760
references.citation: J Inflamm. 1995;45(2):85-96
references.pmid: 7583361
references.citation: J Leukoc Biol. 2007 Sep;82(3):763-73
references.pmid: 17535983
references.citation: Mol Immunol. 2004 Jul;41(6-7):631-43
references.pmid: 15220000
references.citation: FEBS Lett. 2007 May 22;581(11):2098-104
references.pmid: 17382322
references.citation: Science. 2008 May 2;320(5876):674-7
references.pmid: 18403674
references.citation: Cell Death Differ. 2007 Sep;14(9):1583-9
references.pmid: 17599094
references.citation: J Biol Chem. 2005 Jan 14;280(2):1543-51
references.pmid: 15536084
references.citation: J Immunol. 2001 Apr 1;166(7):4664-71
references.pmid: 11254726